Novel Lipids

ABSTRACT

The present invention includes compound having the following structural formula:

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.17/191,214, filed on Mar. 3, 2021, and U.S. patent application Ser. No.16/452,858 filed on Jun. 26, 2019, now U.S. Pat. No. 10,975,111 issuedon Apr. 13, 2021, which claims priority to U.S. Provisional PatentApplication Ser. No. 62/690,196 filed Jun. 26, 2018, the contents ofwhich is incorporated by reference herein in its entirety.

STATEMENT OF FEDERALLY FUNDED RESEARCH

None.

TECHNICAL FIELD OF THE INVENTION

The present invention relates in general to the field of novel lipids toreduce or eliminate cardiopathies, such as QT prolongation, cardiacmuscle damage, or AV block, that are drug-induced or caused by a diseaseor condition.

BACKGROUND OF THE INVENTION

Without limiting the scope of the invention, its background is describedin connection with drug-induced QT prolongation and other cardiopathiesand cardio-toxicities.

There are numerous pharmaceutical agents designed for the treatment ofvarious diseases which are commonly prescribed, despite being known orsuspecting of having adverse effects on the patient's heart. In additionto cardiac arrhythmias, including QT prolongation, supraventriculartachycardias (SVT), and atrial fibrillation (AF), a number of othercardiac toxicities can occur, including cardiac muscle damage,cardiomyopathy, congestive heart failure, and left ventricularhypertrophy (LVH) as a side effect of pharmaceutical agents.

The cardiotoxicity of those pharmaceutical agents can lead tosignificant complications that can affect patients being treated forvarious diseases, such as proliferative malignancies. The severity ofsuch toxicity depends on many factors such as the immediate andcumulative dose, the method of administration, the presence of anyunderlying cardiac condition, and various congenital or acquired cardiacrisk factors unique to a particular patient. Moreover, toxicity can beaffected by current or previous treatment with other pharmaceuticalagents. Cardiotoxic effects can occur immediately during administrationof the drug, or they may not manifest themselves until months or yearsafter the patient has been treated.

High-dose chemotherapy remains the therapy of choice for aggressivemalignancies. Countless clinical studies have demonstrated thathigh-dose chemotherapy can significantly prolong patient survival;however, its use and effectiveness are limited by significant sideeffects, in particular cardiotoxicity. In mid-to-late phase cardiactoxicity, heart failure can appear many years after chemotherapy hasended. Treatment with chemotherapeutic agents is known to result inpericardial and endomyocardial fibrosis, heart failure, myocarditis, orpericarditis. Chemotherapy has also been associated with hemorrhagicmyocardial necrosis and cardiomyopathy.

In addition, antineoplastic monoclonal antibodies are also linked tocardiotoxicity. Infusion-related cardiotoxic effects, such as leftventricular dysfunction, congestive heart failure, and other cardiacdysfunction can occur. The risk of such complications increases if thepatient has preexisting cardiac disease, older age, prior cardiotoxictherapy, or radiation to the chest.

Tyrosine Kinase inhibitors (TKIs) have well known cardiotoxic effects.The antracyclins, trastuzumab, imatinib mesylate, dasatinib, nilotinib,sunitinib, sorafenib vandetanib, and lapatinib have all been associatedwith a range of mechanical and electrical dysfunctions.

Among the toxic effects associated with TKIs are QT prolongation, suddencardiac death (both considered rhythmic dysfunctions), as well ascontractility issues such as reduction in left ventricular ejectionfraction (LVEF), congestive heart failure (CHF), acute coronary disease,hypertension, and myocardial infarction (MI). Given the therapeuticpotential of drugs such as the tyrosine kinase inhibitors, variousstrategies have been used to attempt to mitigate the cardiotoxicity ofcancer treatment. The primary method for preventing cardiac toxicity isto limit the dose of cardiotoxic drugs. There is also some evidence thatthe method of drug administration may affect the risk of cardiactoxicity. Rapid administration of cardio toxic agents results in highblood levels, which may cause more heart damage than the same amount ofdrug given over a longer period of time. Giving smaller doses of drugmore frequently can also decrease the toxicity compared to large dosesof drugs at longer intervals.

The risk of cardiac toxicity from certain chemotherapy agents has beenreduced by encapsulating these drugs in a liposome. For example, studiesindicate that cardiotoxicity is considerably lower with liposomaldoxorubicin formulations than with conventional doxorubicin.

Dexrazoxane is an aminopolycarboxylic acid that has been shown toprevent or reduce the severity of heart damage caused by doxorubicin.Dexrazoxane is thought to protect the heart muscle by blocking theformation of oxygen free radicals. One of the ways that radiation andchemotherapy drugs damage cells is by forming free radicals. Freeradicals are unstable molecules that are formed during many normalcellular processes that involve oxygen, such as burning fuel for energy.They are also formed from exposure to elements in the environment, liketobacco smoke, radiation and chemotherapy drugs.

However, a need remains for new composition and methods for reducingcardiopathies, whether drug-induced, or as a result of a disease orcondition.

SUMMARY OF THE INVENTION

The present invention relates to novel cardiopathy-reducing lipids ofFormula I:

wherein,

R¹ is a C₁-C₂₀ branched or unbranched hydrocarbon possessing 0-10 doublebonds, 0-10 triple bonds or a combination of 0-10 double and triplebonds;

R² is a C₁-C₂₀ branched or unbranched hydrocarbon possessing 0-10 doublebonds, 0-10 triple bonds or a combination of 0-10 double and triplebonds;

R³ is

R⁴ is H or a pharmaceutically acceptable cation, wherein incorporationof said pharmaceutically acceptable cation results in a salt, e.g., amonomeric salt, a dimeric salt, a trimeric salt, or a multimeric salt;

R⁵ is a C₁-C₁₀ branched or unbranched hydrocarbon optionally substitutedwith one or more groups selected from OH, OAc, OMe, NH₂, NHAc, NHMe,N(Me)₂, SH, CN, COOH, CONH₂, Cl, Br and I;

R⁶ is a C₁-C₁₀ branched or unbranched hydrocarbon optionally substitutedwith one or more groups selected from OH, OAc, OMe, NH₂, NHAc, NHMe,N(Me)₂, SH, CN, COOH, CONH₂, Cl, Br and I;

R⁷ is a C₀-C₂₀ branched or unbranched hydrocarbon possessing 0-10 doublebonds, 0-10 triple bonds or a combination of 0-10 double and triplebonds;

R⁸ is H or a C₀-C₂₀ branched or unbranched hydrocarbon possessing 0-10double bonds, 0-10 triple bonds or a combination of 0-10 double andtriple bonds;

X is a direct linkage, CH₂, O or NH;

Y is a direct linkage, CH₂, O or NH; and,

Each stereogenic center is independently R, S or racemic.

Another embodiment of this invention relates to a method of preparing acompound of Formula I

wherein,

R¹ is a C₁-C₂₀ branched or unbranched hydrocarbon possessing 0-10 doublebonds, 0-10 triple bonds or a combination of 0-10 double and triplebonds;

R² is a C₁-C₂₀ branched or unbranched hydrocarbon possessing 0-10 doublebonds, 0-10 triple bonds or a combination of 0-10 double and triplebonds;

R³ is

R⁴ is H or a pharmaceutically acceptable cation, wherein incorporationof said pharmaceutically acceptable cation results in a salt, e.g., amonomeric salt, a dimeric salt, a trimeric salt, or a multimeric salt;

R⁵ is a C₁-C₁₀ branched or unbranched hydrocarbon optionally substitutedwith one or more groups selected from OH, OAc, OMe, NH₂, NHAc, NHMe,N(Me)₂, SH, CN, COOH, CONH₂, Cl, Br and I;

R⁶ is a C₁-C₁₀ branched or unbranched hydrocarbon optionally substitutedwith one or more groups selected from OH, OAc, OMe, NH₂, NHAc, NHMe,N(Me)₂, SH, CN, COOH, CONH₂, Cl, Br and I;

R⁷ is a C₀-C₂₀ branched or unbranched hydrocarbon possessing 0-10 doublebonds, 0-10 triple bonds or a combination of 0-10 double and triplebonds;

R⁸ is H or a C₀-C₂₀ branched or unbranched hydrocarbon possessing 0-10double bonds, 0-10 triple bonds or a combination of 0-10 double andtriple bonds;

X is a direct linkage, CH₂, O or NH;

Y is a direct linkage, CH₂, O or NH; and,

Each stereogenic center is independently R, S or racemic;

Comprising the Steps of:

(1) Converting the hydroxyl groups of a compound of Formula II toesters, carbonates, carbamates, or collectively to an acetal or a ketal

wherein, all substitutions are defined as above; and

(2) Converting a phosphorus-bound OH group to O—R⁴, wherein R⁴ is not H;or Comprising the steps of:

(1) Linking a compound of Formula III with a compound of Formula IV orwith a compound of Formula V through creation of a phosphate diesterbridge

wherein, all substitutions are defined as above; and

(2) Converting a phosphorus-bound OH group to O—R⁴, wherein R⁴ is not H.

In one aspect, R⁴ is H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium ortetraalkylammonium. In another aspect, the compound is selected from thecompound is selected from compounds 1 to 30.

Another embodiment of this invention relates to pharmaceuticalcompositions comprising a compound of Formula I and a pharmaceuticallyacceptable diluent or carrier. The pharmaceutical compositions may alsocomprise one or more agents that induce a cardiopathy as a side effect,wherein the compound reduces or eliminates the cardiopathy. Furthermore,said pharmaceutical compositions may also comprise one or moreexcipients, binders, anti-adherents, coatings, disintegrants, fillers,flavors, dyes, colors, glidants, lubricants, preservatives, sorbents,sweeteners, derivatives thereof, or combinations thereof. In one aspect,R⁴ is H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium. Inone aspect, compound is selected from at least one of:

In another aspect, the compounds exist as a single entity, a solvate, ahydrate, a crystal, an amorphous solid, a liquid, or an oil. In anotheraspect, the composition is in a pharmaceutical composition, which mayfurther comprise one or more agents that induce a cardiopathy as a sideeffect. In another aspect, the agent that induces a cardiopathy as aside effect is selected from at least one of: Albuterol, Alfuzosin,Amantadine, Amiodarone, Amisulpride, Amitriptyline, Amoxapine,Amphetamine, Anagrelide, Apomorphine, Arformoterol, Aripiprazole,Arsenic trioxide, Astemizole, Atazanavir, Atomoxetine, Azithromycin,Bedaquiline, Bepridil, Bortezomib, Bosutinib, Chloral hydrate,Chloroquine, Chlorpromazine, Ciprofloxacin, Cisapride, Citalopram,Clarithromycin, Clomipramine, Clozapine, Cocaine, Curcumin, Crizotinib,Dabrafenib, Dasatinib, Desipramine, Dexmedetomidine, Dexmethylphenidate,Dextroamphetamine, Amphetamine, Dihydroartemisinin and Piperaquine,Diphenhydramine, Diisopyramide, Dobutamine, Dofetilide, Dolasetron,Domperidone, Dopamine, Doxepin, Dronedarone, Droperidol, Ephedrine,Epinephrine, Adrenaline, Eribulin, Erythromycin, Escitalopram,Famotidine, Felbamate, Fenfluramine, Fingolimod, Flecainide,Fluconazole, Fluoxetine, Formoterol, Foscarnet, Fosphenytoin,Furosemide, Frusemide, Galantamine, Gatifloxacin, Gemifloxacin,Granisetron, Halofantrine, Haloperidol, Hydrochlorothiazide, Ibutilide,Iloperidone, Imipramine, Melipramine, Indapamide, Isoproterenol,Isradipine, Itraconazole, Ivabradine, Ketoconazole, Lapatinib,Levalbuterol, Levofloxacin, Levomethadyl, Lisdexamfetamine, Lithium,Mesoridazine, Metaproterenol, Methadone, Methamphetamine,Methylphenidate, Midodrine, Mifepristone, Mirabegron, Mirtazapine,Moexipril/HCTZ, Moxifloxacin, Nelfinavir, Nicardipine, Nilotinib,Norepinephrine, Norfloxacin, Nortriptyline, Ofloxacin, Olanzapine,Ondansetron, Oxytocin, Paliperidone, Paroxetine, Pasireotide, Pazopanib,Pentamidine, Perflutren lipid microspheres, Phentermine, Phenylephrine,Phenylpropanolamine, Pimozide, Posaconazole, Probucol, Procainamide,Promethazine, Protriptyline, Pseudoephedrine, Quetiapine, Quinidine,Quinine sulfate, Ranolazine, Rilpivirine, Risperidone, Ritodrine,Ritonavir, Roxithromycin, Salbutamol, Salmeterol, Saquinavir,Sertindole, Sertraline, Sevoflurane, Sibutramine, Solifenacin,Sorafenib, Sotalol, Sparfloxacin, Sulpiride, Sunitinib, Tacrolimus,Tamoxifen, Telaprevir, Telavancin, Telithromycin, Terbutaline,Terfenadine, Tetrabenazine, Thioridazine, Tizanidine, Tolterodine,Toremifene, Trazodone, Trimethoprim-Sulfa, Trimipramine, Vandetanib,Vardenafil, Vemurafenib, Venlafaxine, Voriconazole, Vorinostat, orZiprasidone. In another aspect, the pharmaceutical composition furthercomprises one or more excipients, binders, anti-adherents, coatings,disintegrants, fillers, flavors, dyes, colors, glidants, lubricants,preservatives, sorbents, sweeteners, derivatives thereof, orcombinations thereof. In another aspect, the binder is selected from thegroup consisting of hydroxypropylmethylcellulose, ethyl cellulose,povidone, acrylic and methacrylic acid co-polymers, pharmaceuticalglaze, gums, and milk derivatives. In another aspect, the pharmaceuticalcomposition comprises a compound of Formula I in an amount per unit doseof between about 1 mg and about 1 gram per unit dose. In another aspect,the pharmaceutical composition is a formulation for oral, sublingual,transdermal, suppository, intrathecal, enteral, parenteral, intravenous,intraperitoneal, cutaneous, subcutaneous, topical, pulmonary, rectal,vaginal, or intramuscular administration. In another aspect, theformulation for oral administration is a tablet, capsule, caplet, pill,powder, troche, lozenge, slurry, liquid solution, suspension, emulsion,elixir or oral thin film (OTF). In another aspect, the formulation is asolid form, a solution, a suspension, or a soft gel form. Thepharmaceutical dosage forms may be selected from oral, sublingual,transdermal, suppository, intrathecal, enteral, parenteral, intravenous,intraperitoneal, cutaneous, subcutaneous, topical, pulmonary, rectal,vaginal, or intramuscular administration.

Another embodiment of this invention provides a method of reducing oreliminating one or more of a cardiac channelopathy, cardiac muscledamage, or a condition resulting from the irregularity or alteration inthe cardiac pattern, in a human or animal subject, comprising the stepof administering to a human or animal subject a compound of Formula I,or any one of compounds 1-30, wherein the compound reduces or eliminatesthe one or more of a cardiac channelopathy or a condition resulting fromthe irregularity or alteration in the cardiac pattern caused by theactive agent used to treat a disease. The composition can be formulatedwith a compounds that causes a channelopathy, cardiac muscle damage, ora condition resulting from the irregularity or alteration in the cardiacpattern, in a human or animal subject, as set forth herein.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the features and advantages of thepresent invention, reference is now made to the detailed description ofthe invention along with the accompanying figures and in which:

FIG. 1 is a graph that shows the effect of an oral single dose ofMoxifloxacin (20 mg/kg) on QTc interval of guinea pigs compared to thesame oral single dose of Moxifloxacin administrated concomitantly withan oral single dose of Compound 1,

FIG. 2 is a graph that shows the effect of an oral single dose ofMoxifloxacin (20 mg/kg) on QTc interval of guinea pigs compared to thesame oral single dose of Moxifloxacin administrated concomitantly withan oral single dose of Compound 6,

FIG. 3 is a graph that shows the effect of an oral single dose ofMoxifloxacin (20 mg/kg) on QTc interval of guinea pigs compared to thesame oral single dose of Moxifloxacin administrated concomitantly withan oral single dose of Compound 4,

FIG. 4 is a graph that shows the effect of an oral single dose ofMoxifloxacin (20 mg/kg) on QTc interval of guinea pigs compared to thesame oral single dose of Moxifloxacin administrated concomitantly withan oral single dose of Compound 2

FIG. 5 is a graph that shows the effect of an oral single dose ofMoxifloxacin (20 mg/kg) on QTc interval of guinea pigs compared to thesame oral single dose of Moxifloxacin administrated concomitantly withan oral single dose of Compound 5,

FIG. 6 is a composite graph that shows the effect of an oral single doseof Moxifloxacin (20 mg/kg) on QTc interval of guinea pigs compared tothe same oral single dose of Moxifloxacin administrated concomitantlywith an oral single dose of Compound 1, Compound 2, Compound 4, Compound5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10 andCompound 11.

FIG. 7 is a depiction of example chemical structures that areembodiments of the present invention.

DETAILED DESCRIPTION OF THE INVENTION 1. General Description of theCompounds in at Least Some Embodiments of the Invention

At least one embodiment of the present invention provides a structure ofFormula I:

wherein,

R¹ is a C₁-C₂₀ branched or unbranched hydrocarbon possessing 0-10 doublebonds, 0-10 triple bonds or a combination of 0-10 double and triplebonds;

R² is a C₁-C₂₀ branched or unbranched hydrocarbon possessing 0-10 doublebonds, 0-10 triple bonds or a combination of 0-10 double and triplebonds;

R³ is

R⁴ is H or a pharmaceutically acceptable cation, wherein incorporationof said pharmaceutically acceptable cation results in a salt, e.g., amonomeric salt, a dimeric salt, a trimeric salt, or a multimeric salt;

R⁵ is a C₁-C₁₀ branched or unbranched hydrocarbon optionally substitutedwith one or more groups selected from OH, OAc, OMe, NH₂, NHAc, NHMe,N(Me)₂, SH, CN, COOH, CONH₂, Cl, Br and I;

R⁶ is a C₁-C₁₀ branched or unbranched hydrocarbon optionally substitutedwith one or more groups selected from OH, OAc, OMe, NH₂, NHAc, NHMe,N(Me)₂, SH, CN, COOH, CONH₂, Cl, Br and I;

R⁷ is a C₀-C₂₀ branched or unbranched hydrocarbon possessing 0-10 doublebonds, 0-10 triple bonds or a combination of 0-10 double and triplebonds;

R⁸ is H or a C₀-C₂₀ branched or unbranched hydrocarbon possessing 0-10double bonds, 0-10 triple bonds or a combination of 0-10 double andtriple bonds;

X is a direct linkage, CH₂, O or NH;

Y is a direct linkage, CH₂, O or NH; and,

Each stereogenic center is independently R, S or racemic.

2. Compounds and Definitions

While the making and using of various embodiments of the presentinvention are discussed in detail below, it should be appreciated thatthe present invention provides many applicable inventive concepts thatcan be embodied in a wide variety of specific contexts. The specificembodiments discussed herein are merely illustrative of specific ways tomake and use the invention and do not delimit the scope of theinvention.

Compounds of the present invention include those described generallyabove, and are further illustrated by the classes, subclasses, andspecies disclosed herein. As used herein, the following definitionsshall apply unless otherwise indicated. In at least some embodiments,the chemical elements are identified in accordance with the PeriodicTable of the Elements, CAS version, Handbook of Chemistry and Physics,75th Ed. Additionally, general principles of organic chemistry aredescribed in “Organic Chemistry”, Thomas Sorrell, University ScienceBooks, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001,the entire contents of which are hereby incorporated by reference.

To facilitate the understanding of this invention, a number of terms aredefined below. Terms defined herein have meanings as commonly understoodby a person of ordinary skill in the areas relevant to the presentinvention.

Terms such as “a”, “an” and “the” are not intended to refer to only asingular entity, but include the general class of which a specificexample may be used for illustration. The terminology herein is used todescribe specific embodiments of the invention, but their usage does notlimit the invention, except as outlined in the claims. Specifically, theuse of the word “a” or “an” when used in conjunction with the term“comprising” in the claims and/or the specification may mean “one,” butit is also consistent with the meaning of “one or more,” “at least one,”and “one or more than one.” The use of the term “or” in the claims isused to mean “and/or” unless explicitly indicated to refer toalternatives only or the alternatives are mutually exclusive, althoughthe disclosure supports a definition that refers to only alternativesand “and/or.” Throughout this application, the term “about” is used toindicate that a value includes the inherent variation of error for thedevice, the method being employed to determine the value, or thevariation that exists among the study subjects.

As used in this specification and claim(s), the words “comprising” (andany form of comprising, such as “comprise” and “comprises”), “having”(and any form of having, such as “have” and “has”), “including” (and anyform of including, such as “includes” and “include”) or “containing”(and any form of containing, such as “contains” and “contain”) areinclusive or open-ended and do not exclude additional, unrecitedelements or method steps. In embodiments of any of the compositions andmethods provided herein, “comprising” may be replaced with “consistingessentially of” or “consisting of”. As used herein, the phrase“consisting essentially of” requires the specified integer(s) or stepsas well as those that do not materially affect the character or functionof the claimed invention. As used herein, the term “consisting” is usedto indicate the presence of the recited integer (e.g., a feature, anelement, a characteristic, a property, a method/process step or alimitation) or group of integers (e.g., feature(s), element(s),characteristic(s), property(ies), method/process steps or limitation(s))only. As used herein, each of the compounds may be used in a formulationor method that comprises one or more components or steps, but may alsobe in a composition or method that consists essentially of the listedcomponents, or even in a composition or method that consists of thelisted components.

The term “or combinations thereof” as used herein refers to allpermutations and combinations of the listed items preceding the term.For example, “A, B, C, or combinations thereof” is intended to includeat least one of: A, B, C, AB, AC, BC, or ABC, and if order is importantin a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB.Continuing with this example, expressly included are combinations thatcontain repeats of one or more item or term, such as BB, AAA, AB, BBC,AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan willunderstand that typically there is no limit on the number of items orterms in any combination, unless otherwise apparent from the context.

As used herein, words of approximation such as, without limitation,“about”, “substantial” or “substantially” refers to a condition thatwhen so modified is understood to not necessarily be absolute or perfectbut would be considered close enough to those of ordinary skill in theart to warrant designating the condition as being present. The extent towhich the description may vary will depend on how great a change can beinstituted and still have one of ordinary skill in the art recognize themodified feature as still having the required characteristics andcapabilities of the unmodified feature. In general, but subject to thepreceding discussion, a numerical value herein that is modified by aword of approximation such as “about” may vary from the stated value byat least ±1, 2, 3, 4, 5, 6, 7, 10, 12 or 15%.

An “alkyl” group refers, in one embodiment, to a saturated aliphatichydrocarbon, including straight-chain, branched-chain and cyclic alkylgroups. In one embodiment, the alkyl group has 1-20 carbons. In anotherembodiment, the alkyl group has 1-15 carbons. In another embodiment, thealkyl group has 1-10 carbons. In another embodiment, the alkyl group has11-20 carbons. In another embodiment, the alkyl group has 5-15 carbons.In yet still another embodiment, the alkyl group has 1-5 carbons. Thealkyl group may be unsubstituted or substituted by one or more groupsselected from halogen, hydroxy, alkoxy, carboxylic acid, aldehyde,carbonyl, amido, cyano, alkylamido, dialkylamido, nitro, amino,alkylamino, dialkylamino, carboxyl, thio and thioalkyl.

An “alkenyl” group refers, in one embodiment, to an unsaturatedhydrocarbon, including straight chain, branched chain and cyclic groupshaving one or more double bonds. The alkenyl group may have one doublebond, two double bonds, three double bonds, etc. In another embodiment,the alkenyl group has 2-20 carbons. In another embodiment, the alkenylgroup has 11-20 carbons. In another embodiment, the alkenyl group has5-15 carbons. In another embodiment, the alkenyl group has 2-5 carbons.In another embodiment, the alkenyl group has 2-10 carbons. In anotherembodiment the alkenyl group is ethenyl (—CH═CH2) Examples of alkenylgroups that may be included are ethenyl, propenyl, butenyl,cyclohexenyl, etc. The alkenyl group may be unsubstituted or substitutedby a halogen, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido,nitro, cyano, amino, alkylamino, dialkylamino, carboxyl, thio and/orthioalkyl.

An “alkynyl” group refers, in one embodiment, to an unsaturatedhydrocarbon, including straight chain, branched chain and cyclic groupshaving one or more triple bonds. The alkynyl group may have one triplebond, two triple bonds, three triple bonds, etc. In another embodiment,the alkynyl group has 2-20 carbons. In another embodiment, the alkynylgroup has 11-20 carbons. In another embodiment, the alkynyl group has5-15 carbons. In another embodiment, the alkynyl group has 2-15 carbons.In another embodiment, the alkynyl group has 2-10 carbons. In anotherembodiment the alkynyl group is ethynyl. Examples of alkenyl groups areethynyl, propynyl, butynyl, cyclohexenyl, etc. The alkynyl group may beunsubstituted or substituted by a halogen, hydroxy, alkoxy carbonyl,cyano, amido, alkylamido, dialkylamido, nitro, amino, alkylamino,dialkylamino, carboxyl, thio and/or thioalkyl.

In one embodiment, the term “halogen” refers, in one embodiment to F, inanother embodiment to Cl, in another embodiment to Br, and in anotherembodiment to I.

A “pharmaceutically acceptable cation” refers in one embodiment to thoseorganic cations or inorganic cations that are pharmaceuticallyacceptable for use in a mammal and are well known in the art. Forexample, inorganic cations or organic cations include but are notlimited to lithium, sodium, potassium, magnesium, calcium, barium, zinc,aluminum, cesium, and amine cations. Amine cations include but are notlimited to cations derived from ammonia, triethylamine, tromethamine(TRIS), triethanolamine, ethylenediamine, glucamine, N-methylglucamine,glycine, lysine, ornithine, arginine, ethanolamine, choline and thelike. In one embodiment, the amine cations are cations wherein X+ is ofthe formula YH+ wherein Y is ammonia, triethylamine, trimethylamine(TRIS), triethanolamine, ethylenediamine, glucamine, N-methylglucamine,glycine, lysine, ornithine, arginine, ethanolamine, choline and thelike. In one embodiment suitable cationic organic or inorganic saltsthat can be used include cationic moieties that can form an ionicassociation with the O moieties on the compound and not significantlyadversely affecting the desired properties of the compound for purposesof the present invention, e.g., increased solubility, stability and thelike. It will be appreciated by those skilled in the art that a compoundof Formula I wherein R⁴ is an organic cation or inorganic cation can beconverted to a compound of formula I comprising one or more differentorganic or inorganic cation.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a 13C- or 14C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention.

As used herein, the term “in vivo” refers to being inside the body. Theterm “in vitro” used as used in the present application is to beunderstood as indicating an operation carried out in a non-livingsystem.

As used herein, the term “treatment” refers to the treatment of theconditions mentioned herein, particularly in a patient who demonstratessymptoms of the disease or disorder.

As used herein, the term “treatment” or “treating” refers to anyadministration of a compound of the present invention and includes (i)inhibiting the disease in an animal that is experiencing or displayingthe pathology or symptomatology of the diseased (i.e., arresting furtherdevelopment of the pathology and/or symptomatology); or (ii)ameliorating the disease in an animal that is experiencing or displayingthe pathology or symptomatology of the diseased (i.e., reversing thepathology and/or symptomatology). The term “controlling” includespreventing treating, eradicating, ameliorating or otherwise reducing theseverity of the condition being controlled.

As used herein, the terms “effective amount” or “therapeuticallyeffective amount” described herein means the amount of the subjectcompound that will elicit the biological or medical response of atissue, system, animal or human that is being sought by the researcher,veterinarian, medical doctor or other clinician.

As used herein, the terms “administration of” or “administering a”compound as used herein should be understood to mean providing acompound of the invention to the individual in need of treatment in aform that can be introduced into that individual's body in atherapeutically useful form and therapeutically useful amount,including, but not limited to: oral dosage forms, such as tablets,capsules, syrups, suspensions, and the like; injectable dosage forms,such as IV, IM, or IP, and the like; transdermal dosage forms, includingcreams, jellies, powders, or patches; buccal dosage forms; inhalationpowders, sprays, suspensions, and the like; and rectal suppositories.

As used herein the term “intravenous administration” includes injectionand other modes of intravenous administration.

As used herein, the term “pharmaceutically acceptable” as used herein todescribe a carrier, diluent or excipient must be compatible with theother ingredients of the formulation and not deleterious to therecipient thereof.

3. Description of Exemplary Embodiments

In one embodiment, the present invention relates to a compound ofFormula I:

wherein,

R¹ is a C₁-C₂₀ branched or unbranched hydrocarbon possessing 0-10 doublebonds, 0-10 triple bonds or a combination of 0-10 double and triplebonds;

R² is a C₁-C₂₀ branched or unbranched hydrocarbon possessing 0-10 doublebonds, 0-10 triple bonds or a combination of 0-10 double and triplebonds;

R³ is

R⁴ is H or a pharmaceutically acceptable cation, wherein incorporationof said pharmaceutically acceptable cation results in a salt, e.g., amonomeric salt, a dimeric salt, a trimeric salt, or a multimeric salt;

R⁵ is a C₁-C₁₀ branched or unbranched hydrocarbon optionally substitutedwith one or more groups selected from OH, OAc, OMe, NH₂, NHAc, NHMe,N(Me)₂, SH, CN, COOH, CONH₂, Cl, Br and I;

R⁶ is a C₁-C₁₀ branched or unbranched hydrocarbon optionally substitutedwith one or more groups selected from OH, OAc, OMe, NH₂, NHAc, NHMe,N(Me)₂, SH, CN, COOH, CONH₂, Cl, Br and I;

R⁷ is a C₀-C₂₀ branched or unbranched hydrocarbon possessing 0-10 doublebonds, 0-10 triple bonds or a combination of 0-10 double and triplebonds;

R⁸ is H or a C₀-C₂₀ branched or unbranched hydrocarbon possessing 0-10double bonds, 0-10 triple bonds or a combination of 0-10 double andtriple bonds;

X is a direct linkage, CH₂, O or NH;

Y is a direct linkage, CH₂, O or NH; and,

Each stereogenic center is independently R, S or racemic.

In one embodiment, the present invention relates to a compound ofFormula I:

wherein,

R¹ is a C₁-C₂₀ branched or unbranched hydrocarbon possessing 0-10 doublebonds, 0-10 triple bonds or a combination of 0-10 double and triplebonds;

R² is a C₁-C₂₀ branched or unbranched hydrocarbon possessing 0-10 doublebonds, 0-10 triple bonds or a combination of 0-10 double and triplebonds;

R³ is

R⁴ is H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium,wherein Li, Na and K form monomeric salts and wherein Mg, Ca, Zn and Csform a salt, e.g., a monomeric salt, a dimeric salt, a trimeric salt, ora multimeric salt;

R⁵ is a C₁-C₁₀ branched or unbranched hydrocarbon optionally substitutedwith one or more groups selected from OH, OAc, OMe, NH₂, NHAc, NHMe,N(Me)₂, SH, CN, COOH, CONH₂, Cl, Br and I;

R⁶ is a C₁-C₁₀ branched or unbranched hydrocarbon optionally substitutedwith one or more groups selected from OH, OAc, OMe, NH₂, NHAc, NHMe,N(Me)₂, SH, CN, COOH, CONH₂, Cl, Br and I;

R⁷ is a C₀-C₂₀ branched or unbranched hydrocarbon possessing 0-10 doublebonds, 0-10 triple bonds or a combination of 0-10 double and triplebonds;

R⁸ is H or a C₀-C₂₀ branched or unbranched hydrocarbon possessing 0-10double bonds, 0-10 triple bonds or a combination of 0-10 double andtriple bonds;

X is a direct linkage, CH₂, O or NH;

Y is a direct linkage, CH₂, O or NH; and,

Each stereogenic center is independently R, S or racemic.

In one embodiment, the present invention relates to a method ofpreparing a compound of Formula I

wherein,

R¹ is a C₁-C₂₀ branched or unbranched hydrocarbon possessing 0-10 doublebonds, 0-10 triple bonds or a combination of 0-10 double and triplebonds;

R² is a C₁-C₂₀ branched or unbranched hydrocarbon possessing 0-10 doublebonds, 0-10 triple bonds or a combination of 0-10 double and triplebonds;

R³ is

R⁴ is H or a pharmaceutically acceptable cation, wherein incorporationof said pharmaceutically acceptable cation results in a salt, e.g., amonomeric salt, a dimeric salt, a trimeric salt, or a multimeric salt;

R⁵ is a C₁-C₁₀ branched or unbranched hydrocarbon optionally substitutedwith one or more groups selected from OH, OAc, OMe, NH₂, NHAc, NHMe,N(Me)₂, SH, CN, COOH, CONH₂, Cl, Br and I;

R⁶ is a C₁-C₁₀ branched or unbranched hydrocarbon optionally substitutedwith one or more groups selected from OH, OAc, OMe, NH₂, NHAc, NHMe,N(Me)₂, SH, CN, COOH, CONH₂, Cl, Br and I;

R⁷ is a C₀-C₂₀ branched or unbranched hydrocarbon possessing 0-10 doublebonds, 0-10 triple bonds or a combination of 0-10 double and triplebonds;

R⁸ is H or a C₀-C₂₀ branched or unbranched hydrocarbon possessing 0-10double bonds, 0-10 triple bonds or a combination of 0-10 double andtriple bonds;

X is a direct linkage, CH₂, O or NH;

Y is a direct linkage, CH₂, O or NH; and,

Each stereogenic center is independently R, S or racemic;

Comprising the Steps of:

(1) Converting the hydroxyl groups of a compound of Formula II toesters, carbonates, carbamates, or collectively to an acetal or a ketal

wherein, all substitutions are defined as above; and

(2) Converting a phosphorus-bound OH group to O—R⁴, wherein R⁴ is not H;or Comprising the steps of:

(1) Linking a compound of Formula III with a compound of Formula IV orwith a compound of Formula V through creation of a phosphate diesterbridge

wherein, all substitutions are defined as above; and

(2) Converting a phosphorus-bound OH group to O—R⁴, wherein R⁴ is not H.

In a preferred embodiment, the present invention relates to a method ofpreparing a compound of Formula I

wherein,

R¹ is a C₁-C₂₀ branched or unbranched hydrocarbon possessing 0-10 doublebonds, 0-10 triple bonds or a combination of 0-10 double and triplebonds;

R² is a C₁-C₂₀ branched or unbranched hydrocarbon possessing 0-10 doublebonds, 0-10 triple bonds or a combination of 0-10 double and triplebonds;

R³ is

R⁴ is H, Li, Na, K, Mg, Ca, Zn, Cs, ammonium or tetraalkylammonium,wherein Li, Na and K form monomeric salts and wherein Mg, Ca, Zn and Csform a salt, e.g., a monomeric salt, a dimeric salt, a trimeric salt, ora multimeric salt;

R⁵ is a C₁-C₁₀ branched or unbranched hydrocarbon optionally substitutedwith one or more groups selected from OH, OAc, OMe, NH₂, NHAc, NHMe,N(Me)₂, SH, CN, COOH, CONH₂, Cl, Br and I;

R⁶ is a C₁-C₁₀ branched or unbranched hydrocarbon optionally substitutedwith one or more groups selected from OH, OAc, OMe, NH₂, NHAc, NHMe,N(Me)₂, SH, CN, COOH, CONH₂, Cl, Br and I;

R⁷ is a C₀-C₂₀ branched or unbranched hydrocarbon possessing 0-10 doublebonds, 0-10 triple bonds or a combination of 0-10 double and triplebonds;

R⁸ is H or a C₀-C₂₀ branched or unbranched hydrocarbon possessing 0-10double bonds, 0-10 triple bonds or a combination of 0-10 double andtriple bonds;

X is a direct linkage, CH₂, O or NH;

Y is a direct linkage, CH₂, O or NH; and,

Each stereogenic center is independently R, S or racemic;

Comprising the steps of:

(1) Converting the hydroxyl groups of a compound of Formula II toesters, carbonates, carbamates, or collectively to an acetal or a ketal

wherein, all substitutions are defined as above; and

(3) Converting a phosphorus-bound OH group to O—R⁴, wherein R⁴ is not H;or Comprising the steps of:

(1) Linking a compound of Formula III with a compound of Formula IV orwith a compound of Formula V through creation of a phosphate diesterbridge

wherein, all substitutions are defined as above; and

(2) Converting a phosphorus-bound OH group to O—R⁴, wherein R⁴ is not H.

As defined generally above, R¹ is a C₁-C₂₀ branched or unbranchedhydrocarbon possessing 0-10 double bonds, 0-10 triple bonds or acombination of 0-10 double and triple bonds. In some embodiments, R¹ isa C₁-C₁₅ branched or unbranched hydrocarbon possessing 0-7 double bonds,0-7 triple bonds or a combination of 0-7 double and triple bonds. Insome embodiments, R¹ is a C₁-C₁₀ branched or unbranched hydrocarbonpossessing 0-5 double bonds, 0-5 triple bonds or a combination of 0-5double and triple bonds. In some embodiments, R¹ is a C₁₁-C₂₀ branchedor unbranched hydrocarbon possessing 0-5 double bonds, 0-5 triple bondsor a combination of 0-5 double and triple bonds. In some embodiments, R¹is a C₅-C₁₅ branched or unbranched hydrocarbon possessing 0-5 doublebonds, 0-5 triple bonds or a combination of 0-5 double and triple bonds.In some embodiments, R¹ is a C₁-C₅ branched or unbranched hydrocarbonpossessing 0-2 double bonds, 0-2 triple bonds or a combination of 0-2double and triple bonds. In some embodiments, le is a C₁₀-C₁₅ branchedor unbranched hydrocarbon.

As defined generally above, R² is a C₁-C₂₀ branched or unbranchedhydrocarbon possessing 0-10 double bonds, 0-10 triple bonds or acombination of 0-10 double and triple bonds. In some embodiments, R² isa C₁-C₁₅ branched or unbranched hydrocarbon possessing 0-7 double bonds,0-7 triple bonds or a combination of 0-7 double and triple bonds. Insome embodiments, R² is a C₁-C₁₀ branched or unbranched hydrocarbonpossessing 0-5 double bonds, 0-5 triple bonds or a combination of 0-5double and triple bonds. In some embodiments, R² is a C₁₁-C₂₀ branchedor unbranched hydrocarbon possessing 0-5 double bonds, 0-5 triple bondsor a combination of 0-5 double and triple bonds. In some embodiments, R²is a C₅-C₁₅ branched or unbranched hydrocarbon possessing 0-5 doublebonds, 0-5 triple bonds or a combination of 0-5 double and triple bonds.In some embodiments, R² is a C₁-C₅ branched or unbranched hydrocarbonpossessing 0-2 double bonds, 0-2 triple bonds or a combination of 0-2double and triple bonds. In some embodiments, R² is a C₁₀-C₁₅ branchedor unbranched hydrocarbon.

As defined generally above, both R¹ and R² have the same definition. Insome embodiments, R¹ and R² are the same. In some embodiments, R¹ and R²are different.

As defined generally above, R³ is

In some embodiments, R³ is

In some embodiments, R³ is

As defined generally above, R⁴ is H or a pharmaceutically acceptablecation, wherein incorporation of said pharmaceutically acceptable cationresults in a salt, e.g., monomeric salt, a dimeric salt, a trimericsalt, or even a multimeric salt. In preferred embodiments, R⁴ is H, Li,Na, K, Mg, Ca, Zn, Cs, ammonium and tetraalkylammonium. In someembodiments, R⁴ is H. In some embodiments, R⁴ is Li. In someembodiments, R⁴ is Na. In some embodiments, R⁴ is K. In someembodiments, R⁴ is Mg. In some embodiments, R⁴ is Ca. In someembodiments, R⁴ is Zn. In some embodiments, R⁴ is Cs. In someembodiments, R⁴ is ammonium. In some embodiments, R⁴ istetraalkylammonium.

As defined generally above, R⁵ is a C₁-C₁₀ branched or unbranchedhydrocarbon optionally substituted with one or more groups selected fromOH, OAc, OMe, NH₂, NHAc, NHMe, N(Me)₂, SH, CN, COOH, CONH₂, Cl, Br andI.

As defined generally above, R⁶ is a C₁-C₁₀ branched or unbranchedhydrocarbon optionally substituted with one or more groups selected fromOH, OAc, OMe, NH₂, NHAc, NHMe, N(Me)₂, SH, CN, COOH, CONH₂, Cl, Br andI;

As defined generally above, both R⁵ and R⁶ have the same definition. Insome embodiments, R⁵ and R⁶ are the same. In some embodiments, R⁵ and R⁶are different.

As defined generally above, R⁷ is a C₁-C₂₀ branched or unbranchedhydrocarbon possessing 0-10 double bonds, 0-10 triple bonds or acombination of 0-10 double and triple bonds. In some embodiments, R⁷ isa C₁-C₁₅ branched or unbranched hydrocarbon possessing 0-7 double bonds,0-7 triple bonds or a combination of 0-7 double and triple bonds. Insome embodiments, R⁷ is a C₁-C₁₀ branched or unbranched hydrocarbonpossessing 0-5 double bonds, 0-5 triple bonds or a combination of 0-5double and triple bonds. In some embodiments, R⁷ is a C₁₁-C₂₀ branchedor unbranched hydrocarbon possessing 0-5 double bonds, 0-5 triple bondsor a combination of 0-5 double and triple bonds. In some embodiments, R⁷is a C₅-C₁₅ branched or unbranched hydrocarbon possessing 0-5 doublebonds, 0-5 triple bonds or a combination of 0-5 double and triple bonds.In some embodiments, R⁷ is a C₁-C₅ branched or unbranched hydrocarbonpossessing 0-2 double bonds, 0-2 triple bonds or a combination of 0-2double and triple bonds. In some embodiments, R⁷ is a C₁₀-C₁₅ branchedor unbranched hydrocarbon.

As defined generally above, R⁸ is H or a C₀-C₂₀ branched or unbranchedhydrocarbon possessing 0-10 double bonds, 0-10 triple bonds or acombination of 0-10 double and triple bonds. In some embodiments, R⁸ isH. In some embodiments, R⁸ is a C₀-C₂₀ branched or unbranchedhydrocarbon possessing 0-10 double bonds, 0-10 triple bonds or acombination of 0-10 double and triple bonds.

As defined generally above, R⁷ and R⁸ are similar. In some embodiments,R⁷ and R⁸ are the same. In some embodiments, R⁷ and R⁸ are different.

As defined generally above, X is a direct linkage, CH₂, O or NH. In someembodiments, X is a direct linkage. In some embodiments, X is CH₂. Insome embodiments, X is O. In some embodiments, X is NH.

As defined generally above, Y is a direct linkage, CH₂, O or NH. In someembodiments, Y is a direct linkage. In some embodiments, Y is CH₂. Insome embodiments, Y is O. In some embodiments, Y is NH.

As defined generally above, both X and Y have the same definition. Insome embodiments, X and Y are the same. In some embodiments, X and Y aredifferent.

As defined generally above, each stereogenic center is independently R,S or racemic.

In different embodiments, the present invention has a structure ofCompounds 1-30.

One embodiment of this invention relates to pharmaceutical compositionscomprising a compound of Formula I and a pharmaceutically acceptablediluent or carrier. In one embodiment, said pharmaceutical compositionscomprise a compound of Formula I in an amount per unit dose of betweenabout 1 mg and about 1 gram. In some embodiments, the amount per unitdose is between about 1 mg and about 500 mg. In some embodiments, theamount per unit dose is between about 500 mg and about 1 gram. In someembodiments, the amount per unit dose is between about 250 mg and about750 mg. In some embodiments, the amount per unit dose is between about50 mg and about 450 mg. In some embodiments, the amount per unit dose isbetween about 100 mg and about 300 mg.

In some embodiments, said pharmaceutical compositions additionallycomprise one or more agents that induce a cardiopathy as a side effect,and wherein the compound of Formula I reduces or eliminates thecardiopathy. In some embodiments, the one or more agents that induce acardiopathy as a side effect are selected from at least one of:Albuterol, Alfuzosin, Amantadine, Amiodarone, Amisulpride,Amitriptyline, Amoxapine, Amphetamine, Anagrelide, Apomorphine,Arformoterol, Aripiprazole, Arsenic trioxide, Astemizole, Atazanavir,Atomoxetine, Azithromycin, Bedaquiline, Bepridil, Bortezomib, Bosutinib,Chloral hydrate, Chloroquine, Chlorpromazine, Ciprofloxacin, Cisapride,Citalopram, Clarithromycin, Clomipramine, Clozapine, Cocaine, Curcumin,Crizotinib, Dabrafenib, Dasatinib, Desipramine, Dexmedetomidine,Dexmethylphenidate, Dextroamphetamine, Amphetamine, Dihydroartemisininand Piperaquine, Diphenhydramine, Diisopyramide, Dobutamine, Dofetilide,Dolasetron, Domperidone, Dopamine, Doxepin, Dronedarone, Droperidol,Ephedrine, Epinephrine, Adrenaline, Eribulin, Erythromycin,Escitalopram, Famotidine, Felbamate, Fenfluramine, Fingolimod,Flecainide, Fluconazole, Fluoxetine, Formoterol, Foscarnet,Fosphenytoin, Furosemide, Frusemide, Galantamine, Gatifloxacin,Gemifloxacin, Granisetron, Halofantrine, Haloperidol,Hydrochlorothiazide, Ibutilide, Iloperidone, Imipramine, Melipramine,Indapamide, Isoproterenol, Isradipine, Itraconazole, Ivabradine,Ketoconazole, Lapatinib, Levalbuterol, Levofloxacin, Levomethadyl,Lisdexamfetamine, Lithium, Mesoridazine, Metaproterenol, Methadone,Methamphetamine, Methylphenidate, Midodrine, Mifepristone, Mirabegron,Mirtazapine, Moexipril/HCTZ, Moxifloxacin, Nelfinavir, Nicardipine,Nilotinib, Norepinephrine, Norfloxacin, Nortriptyline, Ofloxacin,Olanzapine, Ondansetron, Oxytocin, Paliperidone, Paroxetine,Pasireotide, Pazopanib, Pentamidine, Perflutren lipid microspheres,Phentermine, Phenylephrine, Phenylpropanolamine, Pimozide, Posaconazole,Probucol, Procainamide, Promethazine, Protriptyline, Pseudoephedrine,Quetiapine, Quinidine, Quinine sulfate, Ranolazine, Rilpivirine,Risperidone, Ritodrine, Ritonavir, Roxithromycin, Salbutamol,Salmeterol, Saquinavir, Sertindole, Sertraline, Sevoflurane,Sibutramine, Solifenacin, Sorafenib, Sotalol, Sparfloxacin, Sulpiride,Sunitinib, Tacrolimus, Tamoxifen, Telaprevir, Telavancin, Telithromycin,Terbutaline, Terfenadine, Tetrabenazine, Thioridazine, Tizanidine,Tolterodine, Toremifene, Trazodone, Trimethoprim-Sulfa, Trimipramine,Vandetanib, Vardenafil, Vemurafenib, Venlafaxine, Voriconazole,Vorinostat, or Ziprasidone. One of ordinary skill in the art willrecognize that additional agents that induce a cardiopathy exist and maybenefit from inclusion in formulations of the present invention.

In some embodiments, the present invention includes a compositioncomprising an active agent that causes a cardiopathy and a compound ofFormula I represented by one or more compounds of Formula I, forexample, Compounds 1 to 30, as set forth above.

One embodiment of this invention provides a pharmaceutical compositioncomprising a structure of Formula I, for example, Compounds 1 to 30,formulated for oral, sublingual, transdermal, suppository, intrathecal,enteral, parenteral, intravenous, intraperitoneal, cutaneous,subcutaneous, topical, pulmonary, rectal, vaginal, or intramuscularadministration, as set forth above. In some embodiments, the compositionformulated for oral administration is a tablet, capsule, caplet, pill,powder, troche, lozenge, slurry, liquid solution, suspension, emulsion,elixir or oral thin film (OTF). In some embodiments, the composition isa solid form, a solution, a suspension, or a soft gel form.

One embodiment of this invention provides pharmaceutical compositionscomprising an active agent that causes a cardiopathy as a side effectand a compound of Formula I, for example Compounds 1 to 30, as set forthabove.

One embodiment of this invention provides a method of reducing oreliminating one or more of a cardiac channelopathy, cardiac muscledamage, or a condition resulting from the irregularity or alteration inthe cardiac pattern, in a human or animal subject caused by an activeagent used to treat a disease, comprising the steps of: administering tothe human or animal subject a pharmaceutical composition comprising acompound of Formula I, for example, Compounds 1 to 30, as set forthabove.

In some embodiments, said pharmaceutical compositions additionallycomprise one or more excipients, binders, anti-adherents, coatings,disintegrants, fillers, flavors, dyes, colors, glidants, lubricants,preservatives, sorbents, sweeteners, derivatives thereof, orcombinations thereof. In some embodiments, the binder is selected fromthe group consisting of hydroxypropylmethylcellulose, ethyl cellulose,povidone, acrylic and methacrylic acid co-polymers, pharmaceuticalglaze, gums, and milk derivatives.

In one embodiment, said pharmaceutical compositions comprise a compoundof Formula I in an amount per unit dose of between about 1 mg and about1 gram. In some embodiments, the amount per unit dose is between about 1mg and about 500 mg. In some embodiments, the amount per unit dose isbetween about 500 mg and about 1 gram. In some embodiments, the amountper unit dose is between about 250 mg and about 750 mg. In someembodiments, the amount per unit dose is between about 50 mg and about450 mg. In some embodiments, the amount per unit dose is between about100 mg and about 300 mg.

In some embodiments, said pharmaceutical compositions additionallycomprise one or more excipients, binders, anti-adherents, coatings,disintegrants, fillers, flavors, dyes, colors, glidants, lubricants,preservatives, sorbents, sweeteners, derivatives thereof, orcombinations thereof. In some embodiments, the binder is selected fromthe group consisting of hydroxypropylmethylcellulose, ethyl cellulose,povidone, acrylic and methacrylic acid co-polymers, pharmaceuticalglaze, gums, and milk derivatives.

In one embodiment, the present invention includes a composition, apharmaceutical composition, and a method in which the active agent thatcauses a cardiopathy as a side effect is selected from at least one of:Albuterol, Alfuzosin, Amantadine, Amiodarone, Amisulpride,Amitriptyline, Amoxapine, Amphetamine, Anagrelide, Apomorphine,Arformoterol, Aripiprazole, Arsenic trioxide, Astemizole, Atazanavir,Atomoxetine, Azithromycin, Bedaquiline, Bepridil, Bortezomib, Bosutinib,Chloral hydrate, Chloroquine, Chlorpromazine, Ciprofloxacin, Cisapride,Citalopram, Clarithromycin, Clomipramine, Clozapine, Cocaine, Curcumin,Crizotinib, Dabrafenib, Dasatinib, Desipramine, Dexmedetomidine,Dexmethylphenidate, Dextroamphetamine, Amphetamine, Dihydroartemisininand Piperaquine, Diphenhydramine, Diisopyramide, Dobutamine, Dofetilide,Dolasetron, Domperidone, Dopamine, Doxepin, Dronedarone, Droperidol,Ephedrine, Epinephrine, Adrenaline, Eribulin, Erythromycin,Escitalopram, Famotidine, Felbamate, Fenfluramine, Fingolimod,Flecainide, Fluconazole, Fluoxetine, Formoterol, Foscarnet,Fosphenytoin, Furosemide, Frusemide, Galantamine, Gatifloxacin,Gemifloxacin, Granisetron, Halofantrine, Haloperidol,Hydrochlorothiazide, Ibutilide, Iloperidone, Imipramine, Melipramine,Indapamide, Isoproterenol, Isradipine, Itraconazole, Ivabradine,Ketoconazole, Lapatinib, Levalbuterol, Levofloxacin, Levomethadyl,Lisdexamfetamine, Lithium, Mesoridazine, Metaproterenol, Methadone,Methamphetamine, Methylphenidate, Midodrine, Mifepristone, Mirabegron,Mirtazapine, Moexipril/HCTZ, Moxifloxacin, Nelfinavir, Nicardipine,Nilotinib, Norepinephrine, Norfloxacin, Nortriptyline, Ofloxacin,Olanzapine, Ondansetron, Oxytocin, Paliperidone, Paroxetine,Pasireotide, Pazopanib, Pentamidine, Perflutren lipid microspheres,Phentermine, Phenylephrine, Phenylpropanolamine, Pimozide, Posaconazole,Probucol, Procainamide, Promethazine, Protriptyline, Pseudoephedrine,Quetiapine, Quinidine, Quinine sulfate, Ranolazine, Rilpivirine,Risperidone, Ritodrine, Ritonavir, Roxithromycin, Salbutamol,Salmeterol, Saquinavir, Sertindole, Sertraline, Sevoflurane,Sibutramine, Solifenacin, Sorafenib, Sotalol, Sparfloxacin, Sulpiride,Sunitinib, Tacrolimus, Tamoxifen, Telaprevir, Telavancin, Telithromycin,Terbutaline, Terfenadine, Tetrabenazine, Thioridazine, Tizanidine,Tolterodine, Toremifene, Trazodone, Trimethoprim-Sulfa, Trimipramine,Vandetanib, Vardenafil, Vemurafenib, Venlafaxine, Voriconazole,Vorinostat, or Ziprasidone. One of ordinary skill in the art willrecognize that additional agents that induce a cardiopathy exist and maybenefit from inclusion in formulations of the present invention.

In some embodiments, said pharmaceutical compositions are formulated fororal, sublingual, transdermal, suppository, intrathecal, enteral,parenteral, intravenous, intraperitoneal, cutaneous, subcutaneous,topical, pulmonary, rectal, vaginal, or intramuscular administration. Insome embodiments, said pharmaceutical composition formulated for oraladministration is a tablet, capsule, caplet, pill, powder, troche,lozenge, slurry, liquid solution, suspension, emulsion, elixir or oralthin film (OTF). In some embodiments, the composition is a solid form, asolution, a suspension, or a soft gel form. In some embodiments, thesolid form further comprises one or more excipients, binders,anti-adherents, coatings, disintegrants, fillers, flavors, dyes, colors,glidants, lubricants, preservatives, sorbents, sweeteners, derivativesthereof, or combinations thereof. In some embodiments, the binder isselected from the group consisting of hydroxypropylmethylcellulose,ethyl cellulose, povidone, acrylic and methacrylic acid co-polymers,pharmaceutical glaze, gums, and milk derivatives.

In one embodiment, said method provides pharmaceutical compositions thatcomprise a compound of Formula I in an amount per unit dose of betweenabout 1 mg and about 1 gram. In some embodiments, the amount per unitdose is between about 1 mg and about 500 mg. In some embodiments, theamount per unit dose is between about 500 mg and about 1 gram. In someembodiments, the amount per unit dose is between about 250 mg and about750 mg. In some embodiments, the amount per unit dose is between about50 mg and about 450 mg. In some embodiments, the amount per unit dose isbetween about 100 mg and about 300 mg.

In one embodiment, said method provides a pharmaceutical compositionformulated for oral, sublingual, transdermal, suppository, intrathecal,enteral, parenteral, intravenous, intraperitoneal, cutaneous,subcutaneous, topical, pulmonary, rectal, vaginal, or intramuscularadministration. In some embodiments, said pharmaceutical compositionformulated for oral administration is a tablet, capsule, caplet, pill,powder, troche, lozenge, slurry, liquid solution, suspension, emulsion,elixir or oral thin film (OTF). In some embodiments, the composition isa solid form, a solution, a suspension, or a soft gel form. In someembodiments, the solid form further comprises one or more excipients,binders, anti-adherents, coatings, disintegrants, fillers, flavors,dyes, colors, glidants, lubricants, preservatives, sorbents, sweeteners,derivatives thereof, or combinations thereof. In some embodiments, thebinder is selected from the group consisting ofhydroxypropylmethylcellulose, ethyl cellulose, povidone, acrylic andmethacrylic acid co-polymers, pharmaceutical glaze, gums, and milkderivatives.

In one embodiment, said method provides pharmaceutical compositions. Oneembodiment of this invention provides administration of a compound ofFormula I, wherein said compound is a lipid that reduces or eliminatescardiopathies, such as QT prolongation, cardiac muscle damage, or AVblock, that are drug-induced or caused by a disease or condition.

The single most common cause of the withdrawal or restriction of the useof marketed drugs has been QT-interval prolongation associated withpolymorphic ventricular tachycardia, or torsade de pointes, a conditionthat can be fatal.

5-HT3 antagonists block serotonin binding. Aloxi (or palonasitron HCL)is an antiemetic for chemotherapy induced nausea and vomiting, a 5-HT 3antagonist, blocks serotonin binding to 5-HT3. In a study there was nosignificant difference in the QTc intervals during the perioperativeperiod, whether 0.075 mg of palonosetron is administered before or aftersevoflurane anesthesia. Palonosetron may be safe in terms of QTcintervals during sevoflurane anesthesia.

5-HT4 receptor agonist. Cisapride is a gastroprokinetic agent, a drugthat increases motility in the upper gastrointestinal tract. It actsdirectly as a serotonin 5-HT4 receptor agonist and indirectly as aparasympathomimetic. Cisapride dose-dependently prolongs the QTinterval. Neither torsade de pointe nor ventricular tachycardia werenoted when monitoring 33 patients during a higher dose stage.

Histamine Antagonist. Antihistamines used in the treatment of allergyact by competing with histamine for H1-receptor sites on effector cells.They thereby prevent, but do not reverse, responses mediated byhistamine alone.

Pain and Premenstrual Symptom Relief H1 antagonists are most useful inacute exudative types of allergy that present with symptoms of rhinitis,urticaria, and conjunctivitis. Their effect, however, is purelypalliative and confined to the suppression of symptoms attributable tothe histamine-antibody reaction

Pyrilamine is a diuretic first-generation histamine H1 antagonist. Thereis a case of an adolescent with prolonged QT interval after an overdoseof pyrilamine. Reports of deaths resulting from ventriculartachyarrhythmias have been made.

Terfenadine is an antihistamine, used to treat allergies, hives(urticaria), and other allergic inflammatory conditions. The brand nameSeldane is discontinued in the U.S. Rare reports of severecardiovascular adverse effects have been received which includeventricular tachyarrhythmias (torsades de pointes, ventriculartachycardia, ventricular fibrillation, and cardiac arrest), hypotension,palpitations, or syncope.

Loratidine is a first-line antihistamine is a second-generationperipheral histamine H1-receptor blocker. In structure, it is closelyrelated to tricyclic antidepressants, such as imipramine, and isdistantly related to the atypical antipsychotic quetiapine. Someantihistamines, such as mizolastine and ebastine, can prolong the QTinterval and provoke severe cardiac arrhythmias. As of mid 2009 very fewclinical data had been published on the risk of QT prolongation withloratadine. Very rare reported cases of torsades de pointes linked toloratadine mainly appear to involve drug interactions, especially withamiodarone and enzyme inhibitors. There are no reports of QTprolongation attributed to desloratadine, the main metabolite ofloratadine. Patients who have risk factors for torsades de pointes orwho are taking certain enzyme inhibitors should avoid using loratadine.

Astemizole is a long-acting and highly selective H1 antagonist, actingon histamine H-1 receptor and H-3 receptors. It has antipruritic, andanticholinergic effects. It is also afunctional inhibitor of acidsphingomyelinase. An overdose of astemizole predisposes the myocardiumto ventricular dysrhythmias, including torsades de pointes. However,dysrhythmias developed only in patients with corrected QT intervalsgreater than 500 ms.

Calcium channel blocker. Prenylamine is a calcium channel blocker of theamphetamine chemical class that is used as a vasodilator in thetreatment of angina pectoris. Resting ECGs were recorded in 29 patientswith angina pectoris before, during and after treatment with prenylamine180 mg daily. The QT interval became significantly prolonged after oneweek of treatment. The prolongation persisted as long as therapy wascontinued, which was up to 6 months. After withdrawal of treatment theQT interval returned to normal within 2 weeks.

Lidoflazine is a piperazine calcium channel blocker is a coronaryvasodilator with some antiarrhythmic action. As a tricyclicantihistamine, It acts as a selective inverse agonist of peripheralhistamine H1-receptors. It carries a significant risk of QT intervalprolongation and ventricular arrhythmia. Lidoflazine inhibits potentlyHERG current (I(HERG)) recorded from HEK 293 cells stably expressingwild-type HERG (IC(50) of approximately 16 nM). It is approximately13-fold more potent against HERG than verapamil under similar conditionsin preferentially inhibiting activated/open HERG channels. Lidoflazineproduces high affinity blockade of the alpha subunit of the HERG channelby binding to aromatic amino acid residues within the channel pore and,second, that this is likely to represent the molecular mechanism of QTinterval prolongation by this drug.

Bepridil is an antihypertensive drug which disrupts the movement ofcalcium (Ca2+) through calcium channels. While it prolongs the QTinterval. Bepridil prolongs the QT and refractoriness and a linearcorrelation could be demonstrated between the percent change in QTc andrefractory period prolongation. Bepridil in one patient reduced by onethe number of stimuli required to induce VT, but no spontaneousarrhythmias were noted, It possesses antiarrhythmic properties with aminimal proarrhythmic effect.

Antimalarials. Chloroquine-Chlorpheniramine (chloroquine pluschloropheniramine) is a histamine H1 receptor blocker that reverseschloroquine insensitivity in Plasmodium falciparum in vitro,Chloroquine/chloropheniramine produces a higher cure rate thanchloroquine alone. Short QT Syndrome (SQTS) is a sporadic or autosomaldominant disorder characterized by markedly accelerated cardiacrepolarization, ventricular arrhythmias and sudden cardiac death. Todate, mutations in 5 different ion channel genes (KCNH2, KCNQ1, KCNJ2,CACNA1C and CACNB2) have been identified to cause SQTS. The risk ofventricular arrhythmias and sudden death is remarkably high in SQTS withcardiac arrest reported as a presenting symptom in 31% of SQTS subjects.Chloroquine Blocks a Mutant Kir2.1 Channel Responsible for Short QTSyndrome and Normalizes Repolarization Properties in silico.

Halofantrine is an antimalarial agent with a substituted phenanthrene,and is related to the antimalarial drugs quinine and lumefantrine. Itcan be associated with cardiotoxicity. The most dangerous side effect iscardiac arrhythmias: halofantrine causes significant QT prolongation,and this effect is seen even at standard doses. The drug shouldtherefore not be given to patients with cardiac conduction defects andshould not be combined with mefloquine. The mechanism of action ofhalofantrine is unknown.

Quinidine is an antimalarial that acts as a class I antiarrhythmic agent(Ia) in the heart. It is a stereoisomer of quinine, This alkaloiddampens the excitability of cardiac and skeletal muscles by blockingsodium and potassium currents across cellular membranes. It prolongscellular action potential, and decreases automaticity. Quinidine alsoblocks muscarinic and alpha-adrenergic neurotransmission. Quinidinecauses greater QT prolongation in women than in men at equivalent serumconcentrations. This difference may contribute to the greater incidenceof drug-induced torsades de pointes observed in women taking quinidineand has implications for other cardiac and noncardiac drugs that prolongthe QTc interval.

Antipsychotics. First-generation antipsychotics, known as typicalantipsychotics, were discovered in the 1950s. Most second-generationdrugs, known as atypical antipsychotics, have been developed morerecently, although the first atypical antipsychotic, clozapine, wasdiscovered in the 1960s and introduced clinically in the 1970s. Bothgenerations of medication tend to block receptors in the brain'sdopamine pathways, but atypicals tend to act on serotonin receptors aswell. Both generations of medication tend to block receptors in thebrain's dopamine pathways, but atypicals tend to act on serotoninreceptors as well. QTc interval prolongation can occur as a result oftreatment with both conventional and novel antipsychotic medications andis of clinical concern because of its association with the potentiallyfatal ventricular arrhythmia, torsade de pointes.

Pimozide is an antipsychotic drug of the diphenylbutylpiperidine class,Can induce prolongation of the QT interval. Pimozide is contraindicatedin individuals with either acquired, congenital or a family history ofQT interval prolongation. Its use is advised against in individuals withpeople with either a personal or a family history of arrhythmias ortorsades de pointe acts as an antagonist of the D2, D3, and D4 receptorsand the 5-HT7 receptor. It is also a hERG blocker.

Sertindole is an antipsychotic medication. Like other atypicalantipsychotics, it has activity at dopamine and serotonin receptors inthe brain. Abbott Labs first applied for U.S. Food and DrugAdministration (FDA) approval for sertindole in 1996, but withdrew thisapplication in 1998 following concerns over the increased risk of suddendeath from QTc prolongation. In a trial of 2000 patients on takingsertindole, 27 patients died unexpectedly, including 13 sudden deaths.The drug has not been approved by the FDA for use in the USA. In Europe,Sertindole was approved and marketed in 19 countries from 1996, but itsmarketing authorization was suspended by the European Medicines Agencyin 1998 and the drug was withdrawn from the market. In 2002, based onnew data, the EMA's CHMP suggested that Sertindole could be reintroducedfor restricted use in clinical trials, with strong safeguards includingextensive contraindications and warnings for patients at risk of cardiacdysrhythmias, a recommended reduction in maximum dose from 24 mg to 20mg in all but exceptional cases, and extensive ECG monitoringrequirement before and during treatment

Chlorpromazine, marketed as Thorazine and Largactil, is an antipsychoticmedication in the typical antipsychotic class. Its mechanism of actionis not entirely clear but believed to be related to its ability as adopamine antagonist. It also has anti-serotonergic andanti-histaminergic properties. Chlorpromazine is a very effectiveantagonist of D2 dopamine receptors and similar receptors, such as D3and D5. Unlike most other drugs of this genre, it also has a highaffinity for D1 receptors. Electrocardiogram QT corrected intervalprolonged is reported only by a few people who take Thorazine. In astudy of 2,633 people who have side effects while taking Thorazine fromFDA and social media, 5 have electrocardiogram QT corrected intervalprolonged.

Thioridazine is a piperidine typical antipsychotic drug belonging to thephenothiazine drug branded product was withdrawn worldwide in 2005because it caused severe cardiac arrhythmias, however, generic versionsare available in the US. The drug was voluntarily discontinued by itsmanufacturer, Novartis, worldwide because it caused severe cardiacarrhythmias. Thioridazine prolongs the QTc interval in a dose-dependentmanner. The ratio of 5-HT2A to D2 receptor binding is believed todictate whether or not most antipsychotics are atypical or typical. Inthioridazine's case its ratio of 5-HT2A to D2 receptor binding is belowthe level that's believed to be required for atypicality despite itsrelatively low extrapyramidal side effect liability in practice.

Haldol, Haloperidol. A typical antipsychotic medication QT intervalprolongation is meperidine. It is on the WHO Model List of EssentialMedicines, It is the most commonly used typical antipsychotic, Specialcautions: patients at special risk for the development of QTprolongation (hypokalemia, concomitant use of other drugs causing QTAmiodarone: Q-Tc interval prolongation (potentially dangerous change inheart rhythm prolongation).

Mesoridazone is a piperidine neuroleptic drug belonging to the class ofdrugs called phenothiazines, used in the treatment of schizophrenia. Itis a metabolite of thioridazine. Mesoridazine was withdrawn from theUnited States market in 2004 due to dangerous side effects, namelyirregular heart beat and QT-prolongation of the electrocardiogram.

Selective serotonin reuptake inhibitors. Celexa (citalopram) is anantidepressant in a group of drugs called selective serotonin reuptakeinhibitors (SSRIs). Its chemical structure a racemic bicyclic phthalanederivative designated(±)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile,is unrelated to that of other SSRIs, or other available antidepressantagents. Citalopram may cause a condition that affects the heart rhythm(QT prolongation).

Antibiotics. Moxifloxacin is a fourth-generation syntheticfluoroquinolone antibacterial agent. It functions by inhibiting DNAgyrase, a type II topoisomerase, and topoisomerase IV (enzymes necessaryto separate bacterial DNA thereby inhibiting cell replication) may causetorsade de pointes. Coadministration of moxifloxacin with other drugsthat also prolong the QT interval or induce bradycardia (e.g.,beta-blockers, amiodarone) should be avoided. Careful considerationshould be given in the use of moxifloxacin in patients withcardiovascular disease, including those with conduction abnormalities.Drugs that prolong the QT interval may have an additive effect on QTprolongation and lead to increased risk of ventricular arrhythmias.

Pentamidine is an antimicrobial medication given to prevent and treatpneumocystis pneumonia. The exact mechanism of its anti-protozoal actionis unknown (though it may involve reactions with ubiquitin andmitochondrial function. Severe or fatal arrhythmias and heart failureare quite frequent. the aromatic diamidine pentamidine acts viainhibition of hERG channel trafficking. Pentamidine has no acute effectson currents produced by hERG, KvLQT1/mink, Kv4.3, or SCNA5. Afterovernight exposure, however, pentamidine reduces hERG currents andinhibited trafficking and maturation of hERG with IC50 values of 5 to 8μM similar to therapeutic concentrations.

Clarithromycin is an antibiotic made from erythromycin is chemicallyknown as 6-O-methylerythromycin. It is in the macrolide class and worksby stopping the making of protein by some bacteria. It causes QTprolongation or ventricular cardiac arrhythmias, including torsade depointes.

Erythromycin is an antibiotic with common side effects that includeserious side effects arrhythmia with prolonged QT intervals includingtorsades de pointes.

Grepafloxacin is an oral broad-spectrum fluoroquinolone antibacterialagent used to treat bacterial infections. Grepafloxacin was withdrawnworldwide from markets in 1999, owing to its side effect of lengtheningthe QT interval on the electrocardiogram, leading to cardiac events andsudden death.

Sparfloxacin is a fluoroquinolone broad-spectrum antibiotic used in thetreatment of bacterial infections. It has a controversial safetyprofile. The use of sparfloxacin is contraindicated in patients withknown QTc prolongation and in patients treated concomitantly with classIA or III antiarrhythmic drugs. In a study, the maximum plasmaconcentration (Cmax) after the 1200- and 1600-mg doses was lower thanwould be expected for a linear dose relationship. This was also the casewith the mean increase and mean maximum increase in QTc interval.Increases in the QTc interval correlated well with C_(max) but not withAUCo-infinity.

Curcumin (diferuloylmethane) is a bright yellow chemical produced bysome plants. It is the principal curcuminoid of turmeric (Curcuma longa)and exerts antioxidant, anti-inflammatory, antiviral, antibacterial,antifungal, and anti-tumor activities. In whole-cell patch-clampexperiments, curcumin inhibited hERG K+ currents in HEK293 cells stablyexpressing hERG channels in a dose-dependent manner, with IC50 value of5.55 The deactivation, inactivation and the recovery time frominactivation of hERG channels were significantly changed by acutetreatment of 10 μM curcumin.

Antiarrhythmics. Antiarrhythmics are used to suppress abnormal rhythmsof the heart (cardiac arrhythmias), such as atrial fibrillation,ventricular tachycardia, and ventricular fibrillation. Procainamide isan antiarrhythmic class used for the treatment of cardiac arrhythmias.It is classified by the Vaughan Williams classification system as classIa, and is used for both supraventricular and ventricular arrhythmias.It was also detected that the antiarrhythmic drug procainamideinterferes with pacemakers. Because a toxic level of procainamide leadsto decrease in ventricular conduction velocity and increase of theventricular refractory period. This results in a disturbance in theartificial membrane potential and leads to a supraventriculartachycardia, which induces failure of the pacemaker and death. Itinduces rapid block of the batrachotoxin (BTX)-activated sodium channelsof the heart muscle and acts as antagonist to long gating closuresProcainamide belongs to the aminobenzamides, which has similar cardiaceffects as quinidine it has the same toxicity profile as quinidine.

Propafenone is a class 1C anti-arrhythmic medication, which treatsillnesses associated with rapid heartbeats such as atrial andventricular arrhythmias and works by slowing the influx of sodium ionsinto the cardiac muscle cells, causing a decrease in excitability of thecells. Propafenone is more selective for cells with a high rate, butalso blocks normal cells more than class Ia or Ib. Propafenone differsfrom the prototypical class Ic antiarrhythmic in that it has additionalactivity as a beta-adrenergic blocker, which can cause bradycardia.

Methanesulphonanilide (E-4031) is an experimental class IIIantiarrhythmic drug that blocks potassium channels of class IIIantiarrhythmic drug. E-4031 acts on a specific class of voltage-gatedpotassium channels mainly found in the heart, the hERG channels. hERGchannels (Kv11.1) mediate the IKr current, which repolarizes themyocardial cells. The hERG channel is encoded by ether-a-go-go relatedgene (hERG). E-4031 blocks hERG-type potassium channels by binding tothe open channels. Its structural target within the hERG-channel isunclear, but some other methanesulfonanilide class III antiarrhythmicdrugs are known to bind to the S6 domain or C-terminal of thehERG-channel. As E-4031 can prolong the QT-interval, it can cause lethalarrhythmias. So far, one clinical trial has been conducted to test theeffect of E-4031 on prolongation of the QT-interval.

Amiodarone is a class III antiarrhythmic for ventricular fibrillation ortachycardia, prolongs phase 3 of the cardiac action potential.Amiodarone is an antiarrhythmic agent known to cause prolongation ofaction potential duration, which is reflected in the electrocardiogramas a prolongation of the QT. Amiodarone has multiple effects onmyocardial depolarization and repolarization that make it an extremelyeffective antiarrhythmic drug. Its primary effect is to block thepotassium channels, but it can also block sodium and calcium channelsand the beta and alpha adrenergic receptors. Amiodarone significantlyprolongs the QT interval and the QTc value.

Dronedarone is a benzofuran derivative related to amiodarone, is a drugused mainly for cardiac arrhythmias (approved by the FDA in 2009). It isa “multichannel blocker”, however, it is unclear which channel(s) play apivotal role in its success. Dronedarone's actions at the cellular levelare controversial with most studies suggesting an inhibition in multipleoutward potassium currents including rapid delayed rectifier, slowdelayed rectifier and ACh-activated inward rectifier. It is alsobelieved to reduce inward rapid Na current and L-type Ca channels. Thereduction in K current in some studies was shown to be due to theinhibition of K-ACh channel or associated GTP-binding proteins. Areduction of K+ current by 69% led to increased AP duration andincreased effective refractory periods, Displays amiodarone-like classIII antiarrhythmic activity in vitro and in clinical trials. The drugalso appears to exhibit activity in each of the 4 Vaughan-Williamsantiarrhythmic classes. Contraindicated in Concomitant use of drugs orherbal products that prolong the QT interval and may induce Torsade dePointes QTc Bazett interval ≥500 ms, or use with drugs or herbalsupplements that prolong QT interval or increase risk of torsades depoints (Class I or III antiarrhythmic agents, phenothiazines, tricyclicantidepressants, certain oral macrolides, ephedra).

Diisopyramide is an antiarrhythmic medication used in the treatment ofventricular tachycardia. It is a sodium channel blocker and thereforeclassified as a Class 1a anti-arrhythmic agent. Diisopyramide's Class 1aactivity is similar to that of quinidine in that it targets sodiumchannels to inhibit conduction. Diisopyramide depresses the increase insodium permeability of the cardiac Myocyte during Phase 0 of the cardiacaction potential, in turn decreasing the inward sodium current. Thisresults in an increased threshold for excitation and a decreasedupstroke velocity Diisopyramide prolongs the PR interval by lengtheningboth the QRS and P wave duration. Concern about diisopyramide has beenthe hypothetical potential for inducing sudden death from its type 1anti-arrhythmic effects.

Dofetilide is a class III antiarrhythmic agent. Due to thepro-arrhythmic potential of dofetilide, it is only available byprescription from physicians who have undergone specific training in therisks of treatment with dofetilide. In addition, it is only available bymail order or through specially trained local pharmacies Dofetilideworks by selectively blocking the rapid component of the delayedrectifier outward potassium current. There is a dose-dependent increasein the QT interval and the corrected QT interval (QTc). Because of this,many practitioners will initiate dofetilide therapy only on individualsunder telemetry monitoring or if serial EKG measurements of QT and QTccan be performed.

Sotalol is a non-selective competitive beta-adrenergic receptor blockerthat also exhibits Class III antiarrhythmic properties. The U.S. Foodand Drug Administration advises that sotalol only be used for seriousarrhythmias, because its prolongation of the QT interval carries a smallrisk of life-threatening torsade de pointes. Sotalol also acts onpotassium channels and causes a delay in relaxation of the ventricles.By blocking these potassium channels, sotalol inhibits efflux of K+ions, which results in an increase in the time before another electricalsignal can be generated in ventricular myocytes. This increase in theperiod before a new signal for contraction is generated.

Ibutilide is a Class III antiarrhythmic agent that is indicated foracute cardioconversion of atrial fibrillation and atrial flutter andprolongs action potential and refractory period of myocardial cells.Because of its Class III antiarrhythmic activity, there should not beconcomitant administration of Class Ia and Class III agents. Unlike mostother Class III antiarrhythmic drugs, ibutilide does not produce itsprolongation of action potential via blockade of cardiac delayedrectifier of potassium current, nor does it have a sodium-blocking,antiadrenergic, and calcium blocking activity that other Class IIIagents possess. Thus, it is often referred as a “pure” Class IIIantiarrhythmic drug. Ibutilide, like other class III antiarrhythmicdrugs, blocks delayed rectified potassium current. It does have actionon the slow sodium channel and promotes the influx of sodium throughthese slow channels. Like other antiarrhythmics, ibutilide can lead toabnormal heart rhythms due to its ability to prolong the QT interval,which can lead to the potentially fatal abnormal heart rhythm known astorsades de pointes. The drug is contraindicated in patients that arelikely to develop abnormal heart rhythms; persons that have hadpolymorphic ventricular tachycardia in the past, have a long QTinterval, sick sinus syndrome, or a recent myocardial infarction, amongothers.

Dopamine receptor antagonists. A dopamine antagonist (antidopaminergic)is a type of drug that blocks dopamine receptors by receptor antagonism.Most antipsychotics are dopamine antagonists, and as such they havefound use in treating schizophrenia, bipolar disorder, and stimulantpsychosis. Several other dopamine antagonists are antiemetics used inthe treatment of nausea and vomiting.

Droperidol is an antidopaminergic butyrophenone, used as an antiemeticand antipsychotic, and is a potent D2 (dopamine receptor) antagonistwith some histamine and serotonin antagonist activity. There areconcerns about QT prolongation and torsades de pointes. The evidence forthis is disputed, with 9 reported cases of torsades in 30 years and allof those having received doses in excess of 5 mg. QT prolongation is adose-related effect, and it appears that droperidol is not a significantrisk in low doses, however, prolongation of QT interval leads totorsades de pointes.

Domperidone is a peripherally selective dopamine D2 receptor antagonistthat is a drug useful in Parkinson's disease, caution is needed due tothe cardiotoxic side effects of domperidone especially when givenintravenously, in elderly people and in high doses (>30 mg per day). Aclinical sign of domperidone's potential toxicity to the heart is theprolongation (lengthening) of the QT interval (a segment of the heart'selectrical pattern). Domperidone use is associated with an increasedrisk of sudden cardiac death (by 70%) most likely through its prolongingeffect of the cardiac QT interval and ventricular arrhythmias. The causeis thought to be blockade of hERG voltage-gated potassium channels. Therisks are dose-dependent, and appear to be greatest with high/very highdoses via intravenous administration and in the elderly, as well as withdrugs that interact with domperidone and increase its circulatingconcentrations (namely CYP3A4 inhibitors). Conflicting reports exist,however. In neonates and infants, QT prolongation is controversial anduncertain.

Anticancer agents. Doxorubicin and anthracycline prolongation of QTc,increased QT dispersion and development of late potentials areindicative of doxorubicin-induced abnormal ventricular depolarizationand repolarization. QT dispersion and late potentials are both known tobe associated with increased risk of serious ventricular dysrhythmiasand sudden death in various cardiac diseases.

Arsenic trioxide is an anti-leukemic can prolong the QTc interval.Cardiac Conduction Abnormalities: Before initiating therapy, perform a12-lead ECG, assess serum electrolytes and creatinine, correctpreexisting electrolyte abnormalities, and consider discontinuing drugsknown to prolong QT interval. Arsenic trioxide can cause QT intervalprolongation and complete atrioventricular block. QT prolongation canlead to a torsade de pointes-type ventricular arrhythmia, which can befatal. The risk of torsade de pointes is related to the extent of QTprolongation, concomitant administration of QT prolonging drugs, ahistory of torsade de pointes, preexisting QT interval prolongation,congestive heart failure, administration of potassium-wasting diuretics,or other conditions that result in hypokalemia or hypomagnesemia. Onepatient (also receiving amphotericin B) had torsade de pointes duringinduction therapy for relapsed APL with arsenic trioxide. Arsenictrioxide (As₂O₃) used in the treatment of acute promyelocytic leukemiareduced hERG/IKr currents not by direct block, but by inhibiting theprocessing of hERG protein in the endoplasmic reticulum (ER) therebydecreasing surface expression of hERG.

Opioids. Levomethadyl is a levo isomer of α-methadyl acetatea syntheticopioid similar in structure to methadone. It has a long duration ofaction due to its active metabolites. In 2001, levacetylmethadol wasremoved from the European market due to reports of life-threateningventricular rhythm disorders.

Methadone is an opioid used to treat pain and drug addiction. Seriousrisks include opioid abuse and heart arrhythmia may also occur includingprolonged QT. The number of deaths in the United States involvingmethadone poisoning was 4,418 in 2011, which was 26% of total deathsfrom opioid poisoning.

Hypolipidemic agents. Lovastatin is a drug used for lowering cholesterolan inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAreductase), an enzyme that catalyzes the conversion of HMG-CoA tomevalonate. Mevalonate is a required building block for cholesterolbiosynthesis and lovastatin interferes with its production by acting asa reversible competitive inhibitor for HMG-CoA, which binds to theHMG-CoA reductase. QTc prolongation associated with antipsychoticmedication occurs in a dose-dependent manner. The addition of lovastatincauses an increase in plasma quetiapine levels through competitiveinhibition of the cytochrome P(450) (CYP) isoenzyme 3A4. This highlightsthe potential for a drug interaction between quetiapine and lovastatinleading to QTc prolongation during the management of dysipidemia inpatients with schizophrenia.

Probucol is an anti-hyperlipidemic drug initially developed in thetreatment of coronary artery disease. Probucol is associated with QTinterval prolongation. Probucol aggravates long QT syndrome associatedwith a novel missense mutation M124T in the N-terminus of HERG.

Channelopathies. The human ether-à-go-go gene related cardiac tetramericpotassium channel, when mutated, can render patients sensitive to over163 drugs, which inhibit ion conduction and deregulate actionpotentials. Prolongation of the action potential follows effects in thepotassium channel. Ion channel active drugs may directly increase theQTc interval, and increase the risk of torsade de point and suddencardiac death. Exacerbation of cardiomyocyte potassium channelsensitivity to drugs may also be associated with metabolic diseasedstates including diabetes or may be of idiopathic origin.

As used herein, the term “liposome” refers to a capsule wherein the wallor membrane thereof is formed of one or more of the novel lipids of thepresent invention. The lipids of the present invention can be used aloneor in conjunction with other, known lipids. In one specific non-limitingexample the novel lipids form, or are used in, liposomes that are emptyliposomes and can be formulated from a single type of phospholipid orcombinations of phospholipids. The empty liposomes can further includesone or more surface modifications, such as proteins, carbohydrates,glycolipids or glycoproteins, and even nucleic acids such as aptamers,thio-modified nucleic acids, protein nucleic acid mimics, proteinmimics, stealthing agents, etc. In one embodiment, the novel liposome ornovel liposome precursor comprising a novel lipid-monoglyceride-fattyacid eutectic, such as a eutectic that includes: lysophosphatidylcompound, a monoglyceride, and free fatty acid, and in certain aspectsthe ratios of the composition are 1:4:2, 1:3:3, 2:4:2, or 1:2:4 molepercent novel lipid:monoglyceride:free fatty acid. The composition maycomprise a eutectic mixture comprising a novel lipid, a myristoylmonoglyceride, and a myristic acid. In one specific, non-limitingexample the composition also comprises an active agent in or about thenovel lipid liposome, which can be an empty liposome, and thecomposition has a ratio of phospholipids to active agent of 3:1, 1:1,0.3:1, and 0.1:1.

Prior work from the some of the present inventors has demonstrated thatformulation with a liposome containing1,2-Dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC),1,2-Dimyristoyl-sn-glycero-3-phosphorylglycerol (DMPG), DMPC/DMPG,1-Myristoyl-2-Hydroxy-sn-Glycero-3-Phosphocholine,12-Mysteroyl-2-Hydroxy-sn-Glycero-3-[Phospho-rac-(glycerol)],1-myristoyl-2-hydroxy-sn-glycero-3-phospho-(1′-rac-glycerol) (LysoPG),12-Mysteroyl-2-Hydroxy-sn-Glycero-3-[Phospho-rac-(glycerol)],1-myristoyl-2-hydroxy-sn-glycero-3-phospho-(1′-rac-glycerol) (LysoPG),or 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine (LysoPC),lysophosphatidylcholine, lauroyl-lysophosphatidylcholine,myristoyl-lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine,stearoyl-lysophosphatidylcholine, arachidoyl-lysophosphatidylcholine,oleoyl-lysophosphatidylcholine, linoleoyl-lysophosphatidylcholine,linolenoyl-lysophosphatidylcholine or erucoyl-lysophosphatidylcholine,prevented hERG channel inhibition by a variety of QT prolonging agents.

More than 20 QTc-prolonging drugs have had their QTc prolongationeliminated in various regulatory-validated preclinical models using theabove lipids.

The present invention demonstrates an enhanced effect in reducing, oreliminating, QT prolongation in a guinea pig model system. The guineapig model system used herein is the closes model system to thefunctioning of the human heart and is well-accepted for testing of QTprolonging agents. Briefly, guinea pigs were instrumented with ECGleads, and administered increasing oral doses of moxifloxacin. Guineapigs are the preferred species in Europe and Canada for QT prolongationtesting, because they possess a complement of cardiac ion channels mostsimilar to that of humans, and are exquisitely sensitive toproarrhythmic drugs. On the drug side, Moxifloxacin is the preferredQTc-prolonging positive control drug in Thorough QT (TQT) clinicalstudies because it causes a dose-dependent QTc prolongation in allspecies, and exhibits very linear pharmacokinetics, making it easy todose and relatively safe at sub-toxic exposure levels.

Those guinea pigs administered only moxifloxacin exhibited severe (+10ms) and life-threatening (+30 ms) QTc prolongation. In contrast, thoseanimals that had received a concomitant dose of, as an example, 14:0lyso PG, exhibited no, or very little, changes in QTc. There resulted astatistically significant right-shift in the QTc-dose response ofMoxifloxacin, actually preventing the QTc prolongation from becomingdose-limiting.

AV block represents an interesting conundrum in cardiology: drug-inducedAV block patients are not treated by pacemaker implantation, unlikepatients suffering from disease-induced AV block. Yet, there is evidencethat drug-induced AV block is irreversible after drug discontinuation in56% of cases (Zeltser D, Justo D, Halkin A, et al. Drug-inducedatrioventricular block: prognosis after discontinuation of the culpritdrug. J Am Coll Cardiol. 2004; 44(1): 105-108). Current practice is toimmediately discontinue AV blocking drugs upon discovering the effect.This withdraws useful, efficient drugs from the pharmacopeia availableto oncologists, while directly impacting drug adoption in the clinic.

The ionic channels involved in AV block and QTc prolongation arecompletely distinct: sodium (Na⁺) and calcium (Ca²⁺) channel inhibitionare responsible for the onset of AV block, while delays inrepolarization due to potassium (K⁺) inhibition lead to QTcprolongation. Yet, the hypothesized mechanism by which lipids rescues K⁺currents could also benefit Na⁺ and Ca²⁺ currents.

To test this hypothesis, guinea pigs were instrumented (subcutaneous ECGleads) and exposed to increasing intravenous doses of Fingolimod and/orverapamil, without and with an oral dose of 14:0 lyso PG. ECG signalswere recorded continuously for 2 hours post-dose for the AV blockersFingolimod and verapamil. PR intervals were measured following theinfusion of Fingolimod. Measurements of PR were stopped when the P wavedisconnected from the QRS complexes, indicating 3rd degree AV block.

Guinea pigs exposed to an intravenous infusion of Fingolimod alonetransitioned to 1st degree AV block as of a dose of 15 μg/kg, whichrapidly progressed to a Mobitz Type-1,2nd-degree AV block at 20 μg/kg,and finally progressed to 3rd degree AV block as of a dose of 23 μg/kg.The progression of the AV block was rapid and irreversible: stoppinginfusion did not prevent the onset of P-QRS dissociation.

The cohort of guinea pigs exposed to verapamil received an i.v.injection of 0.5 mg/kg, followed 60 minutes later by an intravenousinfusion of Fingolimod. A 1st-degree AV block appeared at a dose of 7μg/kg, changed to a Mobitz-Type-1 2nd degree AV block at 10 μg/kg, andtransitioned to 3rd-degree dissociation between P waves and QRScomplexes as of 45 μg/kg.

The third cohort of animals received an initial oral gavage of 1.0 mg/kg14:0 lyso PG, followed 60 minutes later by an intravenous dose of 0.5mg/kg verapamil. Sixty (60) minutes post-verapamil, Fingolimod wasinfused into the animals as described above. The animals exhibitedmodest changes in PR intervals up to a dose of 200 Wkg, at which point a1s-degree AV block appeared. A Mobitz-Type-2 AV block appeared in 2 outof 6 animals with P-QRS dissociation observed at a dose of 51 μg/kg inthose two animals, and at 300 μg/kg in the rest of the animals in thecohort.

In human patients, Fingolimod is counter-indicated in patientspresenting a history of Mobitz Type II second-degree or third-degree AVblock or sick sinus syndrome. The drug has been shown to produce AVblock from the first dose, and avoiding treatment with Fingolimod and AVblockers is recommended (Fingolimod (Fingolimod) Full PrescribingInformation. Novartis: T2016-22, February 2016). Given the history oftranslatability of the guinea pig cardiovascular data to other species,including man, these results suggest that 14:0 lyso PG could alleviatethe risk of AV block associated with Fingolimod use, thus enhancing thesafety profile of the drug, and allowing the treatment of patients,which cannot otherwise receive Fingolimod due to AV block issues.

FIG. 1 is a graph that shows the effect of an oral single dose ofMoxifloxacin (20 mg/kg) on QTc interval of guinea pigs compared to thesame oral single dose of Moxifloxacin administrated concomitantly withan oral single dose of Compound 1.

FIG. 2 is a graph that shows the effect of an oral single dose ofMoxifloxacin (20 mg/kg) on QTc interval of guinea pigs compared to thesame oral single dose of Moxifloxacin administrated concomitantly withan oral single dose of Compound 6.

FIG. 3 is a graph that shows the effect of an oral single dose ofMoxifloxacin (20 mg/kg) on QTc interval of guinea pigs compared to thesame oral single dose of Moxifloxacin administrated concomitantly withan oral single dose of Compound 4.

FIG. 4 is a graph that shows the effect of an oral single dose ofMoxifloxacin (20 mg/kg) on QTc interval of guinea pigs compared to thesame oral single dose of Moxifloxacin administrated concomitantly withan oral single dose of Compound 2.

FIG. 5 is a graph that shows the effect of an oral single dose ofMoxifloxacin (20 mg/kg) on QTc interval of guinea pigs compared to thesame oral single dose of Moxifloxacin administrated concomitantly withan oral single dose of Compound 5.

FIG. 6 is a composite graph that shows the effect of an oral single doseof Moxifloxacin (20 mg/kg) on QTc interval of guinea pigs compared tothe same oral single dose of Moxifloxacin administrated concomitantlywith an oral single dose of Compound 1, Compound 2, Compound 4, Compound5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10 andCompound 11.

FIG. 7 is a depiction of example chemical structures which areembodiments of the present invention.

The novel lipids of the present invention may be manufactured in anative form, or in the form of a salt, hydrate, or solvate thereof salt.Salts further include, by way of example only, lithium, sodium,potassium, calcium, magnesium, ammonium, tetraalkylammonium, and thelike.

In at least some embodiments of the present invention, compounds ofFormula I are prepared according to the following schemes. Forreference, all variable groups included in the following schemes relateto the corresponding variables defined generally above. One of ordinaryskill in the art will recognize that alternative reagents and reactantscan be used to generate the same target compounds and intermediates.

As illustrated in Scheme 1, compounds of Formula VI are reacted withanhydrides followed by subsequent salt formation giving compounds ofFormula VII. One of ordinary skill in the art will recognize thatalternatives to anhydrides will produce similar results. Suchalternatives include, but are not limited to, acid chlorides, acylimidazoles, acyl succinimides and the like. Additionally, one ofordinary skill in the art will recognize that carboxylic acids in thepresence of activating agents will produce similar results. Suitableactivating agents include, but are not limited to, DCC, EDC, HBTU, BOP,PyBOP, carbonyl diimidazole, disuccinimidyl carbonate and the like. Oneof ordinary skill in the art will recognize that alternatives to DOWEXNa⁺ resin for salt formation are useful. Such alternatives include, butare not limited to, sodium bicarbonate, sodium carbonate and the like.One of ordinary skill in the art will recognize that compounds ofFormula VII include compounds 1, 7, 8 and 9.

As illustrated in Scheme 2, compounds of Formula VI are reacted withchloroformates followed by subsequent salt formation giving compounds ofFormula VIII. One of ordinary skill in the art will recognize thatalternatives to chloroformates will produce similar results. Suchalternatives include, but are not limited to, pyrocarbonates and thelike. One of ordinary skill in the art will recognize that bases otherthan triethylamine are useful in carbonate formation reactions. Suchbases include, but are not limited to, triisopropylamine,diisopropylethylamine, DBU, N-methylmorpholine, N-methylpyridine,N,N-dimethylpiperazine and the like. One of ordinary skill in the artwill recognize that acyl transfer catalysts other than DMAP are usefulin carbonate formation reactions. Such acyl transfer catalysts include,but are not limited to, pyridine, 2-methylpyridine and the like.Additionally, one of ordinary skill in the art will recognize thatintroduction of Lewis acid catalysts may facilitate carbonate formation.Such Lewis acid catalysts include, but are not limited to, zincchloride, zinc acetate, zinc bromide, aluminum trichloride, titaniumtrichloride, titanium isopropoxide, boron trifluoride, tin chloride,alumina, silica gel and the like. One of ordinary skill in the art willrecognize that alternatives to sodium bicarbonate for salt formation areuseful. Such alternatives include, but are not limited to, DOWEX Na⁺resin, sodium carbonate and the like. One of ordinary skill in the artwill recognize that compounds of Formula VIII include compounds 2 and 3.

As illustrated in Scheme 3, compounds of Formula VI are reacted withisocyanates followed by subsequent salt formation giving compounds ofFormula IX. One of ordinary skill in the art will recognize thatalternatives to isocyanates will produce similar results. One ofordinary skill in the art will recognize that bases can facilitatecarbamate formation. Such bases include, but are not limited to,triethylamine, triisopropylamine, diisopropylethylamine, DBU,N-methylmorpholine, N-methylpyridine, N,N-dimethylpiperazine and thelike. One of ordinary skill in the art will recognize that acyl transfercatalysts can facilitate carbamate formation. Such acyl transfercatalysts include, but are not limited to, DMAP, pyridine,2-methylpyridine and the like. Additionally, one of ordinary skill inthe art will recognize that introduction of Lewis acid catalysts mayfacilitate carbamate formation. Such Lewis acid catalysts include, butare not limited to, zinc chloride, zinc acetate, zinc bromide, aluminumtrichloride, titanium trichloride, titanium isopropoxide, borontrifluoride, tin chloride, alumina, silica gel and the like. One ofordinary skill in the art will recognize that alternatives to sodiumbicarbonate for salt formation are useful. Such alternatives include,but are not limited to, DOWEX Na⁺ resin, sodium carbonate and the like.

As illustrated in Scheme 4, compounds of Formula X are reacted withanhydrides, chloroformates or isocyanates followed by subsequentcleavage of the benzyl ether protecting group giving compounds ofFormula XI. Coupling of compounds of Formula XI with compounds ofFormula XII using Phospholipase D generates compounds of Formula XIII.One of ordinary skill in the art will recognize that for compounds ofFormula IX alternatives to anhydrides will produce similar results. Suchalternatives include, but are not limited to, acid chlorides, acylimidazoles, acyl succinimides and the like. Additionally, one ofordinary skill in the art will recognize that for compounds of FormulaIX carboxylic acids in the presence of activating agents will producesimilar results. Suitable activating agents include, but are not limitedto, DCC, EDC, HBTU, BOP, PyBOP, carbonyl diimidazole, disuccinimidylcarbonate and the like. One of ordinary skill in the art will recognizethat for compounds of Formula IX alternatives to chloroformates willproduce similar results. Such alternatives include, but are not limitedto, pyrocarbonates and the like. One of ordinary skill in the art willrecognize that for compounds of Formula IX alternatives to isocyanateswill produce similar results. One of ordinary skill in the art willrecognize that bases can facilitate ester, carbonate and carbamateformation. Such bases include, but are not limited to, triethylamine,triisopropylamine, diisopropylethylamine, DBU, N-methylmorpholine,N-methylpyridine, N,N-dimethylpiperazine and the like. One of ordinaryskill in the art will recognize that acyl transfer catalysts canfacilitate ester, carbonate and carbamate formation. Such acyl transfercatalysts include, but are not limited to, DMAP, pyridine,2-methylpyridine and the like. Additionally, one of ordinary skill inthe art will recognize that introduction of Lewis acid catalysts mayfacilitate ester, carbonate and carbamate formation. Such Lewis acidcatalysts include, but are not limited to, zinc chloride, zinc acetate,zinc bromide, aluminum trichloride, titanium trichloride, titaniumisopropoxide, boron trifluoride, tin chloride, alumina, silica gel andthe like. One of ordinary skill in the art will recognize thatalternatives to the benzyl ether protecting group, and associatedreaction conditions for their cleavage, are useful. Various appropriatealcohol protecting groups are broadly described in “Green's ProtectiveGroups in Organic Synthesis”. Such benzyl ether alternatives include,but are not limited to, trimethylsilyl ethers, tert-butyl dimethylsilylethers, triisopropylsilyl ethers, tert-butyl diphenylsilyl ethers,acetates, benzoates, 4-nitrobenzoates, tert-butyl ethers,4-methoxybenzyl ethers and the like. One of ordinary skill in the artwill recognize that alternative enzyme and alternate enzyme reactionconditions are useful in the enzymatic formation of phospho diesters.One of ordinary skill in the art will recognize that compounds ofFormula XIII include compounds 1, 2, 3, 7, 8 and 9.

As illustrated in Scheme 5, compounds of Formula VI are reacted withacetals, ketals, aldehydes or ketones in the presence of an acidcatalyst followed by subsequent salt formation giving compounds ofFormula XIV. One of ordinary skill in the art will recognize thatalternatives to acetals, ketals, aldehydes or ketones will producesimilar results. Such alternatives include, but are not limited to,vinyl ethers and the like. Additionally, one of ordinary skill in theart will recognize that while p-toluenesulfonic acid is an appropriateacid catalyst for the formation of acetals and ketals, alternative acidcatalysts are also useful. Such alternatives to p-toluenesulfonic acidinclude, but are not limited to, PPTS, sulfuric acid, methanesulfonicacid, Amberlyst resin, DOWEX acid resin, silica gel and the like.Furthermore, one of ordinary skill in the art will recognize that acompound of Formula XIV can be converted into an alternate compound ofFormula XIV on reaction with an alternate acetal, ketal, aldehyde orketone in the presence of an acid catalyst. One of ordinary skill in theart will recognize that alternatives to DOWEX Na⁺ resin for saltformation are useful. Such alternatives include, but are not limited to,sodium bicarbonate, sodium carbonate and the like. One of ordinary skillin the art will recognize that compounds of Formula XIV includecompounds 4, 5, 6 and 12.

As illustrated in Scheme 6, compounds of Formula X are reacted withacetals, ketals, aldehydes or ketones in the presence of an acidcatalyst followed by subsequent cleavage of the benzyl ether protectinggroup giving compounds of Formula XV. Coupling of compounds of FormulaXV with compounds of Formula XII using Phospholipase D generatescompounds of Formula XVI. One of ordinary skill in the art willrecognize that for compounds of Formula XV alternatives to acetals,ketals, aldehydes or ketones will produce similar results. Suchalternatives include, but are not limited to, vinyl ethers and the like.Additionally, one of ordinary skill in the art will recognize that whilep-toluenesulfonic acid is an appropriate acid catalyst for the formationof acetals and ketals, alternative acid catalysts are also useful. Suchalternatives to p-toluenesulfonic acid include, but are not limited to,PPTS, sulfuric acid, methanesulfonic acid, Amberlyst resin, DOWEX acidresin, silica gel and the like. Furthermore, one of ordinary skill inthe art will recognize that a compound of Formula XV can be convertedinto an alternate compound of Formula XV on reaction with an alternateacetal, ketal, aldehyde or ketone in the presence of an acid catalyst.One of ordinary skill in the art will recognize that alternatives to thebenzyl ether protecting group, and associated reaction conditions fortheir cleavage, are useful. Various appropriate alcohol protectinggroups are broadly described in “Green's Protective Groups in OrganicSynthesis”. Such benzyl ether alternatives include, but are not limitedto, trimethylsilyl ethers, tert-butyl dimethylsilyl ethers,triisopropylsilyl ethers, tert-butyl diphenylsilyl ethers, acetates,benzoates, 4-nitrobenzoates, tert-butyl ethers, 4-methoxybenzyl ethersand the like. One of ordinary skill in the art will recognize thatalternative enzyme and alternate enzyme reaction conditions are usefulin the enzymatic formation of phospho diesters. One of ordinary skill inthe art will recognize that compounds of Formula XVI include compounds4, 5, 6 and 12.

Scheme 7, Scheme 8, Scheme 9, Scheme 10 and Scheme 11 collectivelyillustrate preparation of compounds of Formula XXVII. As illustrated inScheme 7, a compound of Formula XVII is converted to a benzyl ethergiving a compound of Formula XVIII. The ketal of a compound of FormulaXVIII is then cleaved giving a compound of Formula XIX. On reaction withone or more carboxylic acids and an appropriate activating reagent, acompound of Formula XIX is converted to a compound of Formula XX.Subsequent cleavage of the benzyl ether of a compound of Formula XXgives a compound of Formula XXI. One of ordinary skill in the art willrecognize that alternate reagents and reaction conditions are useful forformation of a benzyl ether. One of ordinary skill in the art will alsorecognize that alternatives to the benzyl ether protecting group, andassociated reaction conditions for their formation, are useful. Variousappropriate alcohol protecting groups are broadly described in “Green'sProtective Groups in Organic Synthesis”. Such benzyl ether alternativesinclude, but are not limited to, trimethylsilyl ethers, tert-butyldimethylsilyl ethers, triisopropylsilyl ethers, tert-butyl diphenylsilylethers, acetates, benzoates, 4-nitrobenzoates, tert-butyl ethers,4-methoxybenzyl ethers and the like. Similarly, one of ordinary skill inthe art will recognize that alternative reaction conditions are usefulfor the cleavage of acetals and ketals. Such conditions are generallydescribed in Green's “Protective Groups in Organic Synthesis”. One ofordinary skill in the art will recognize that carboxylic acids andassociated activating agents are useful for the formation of esters. Oneof ordinary skill in the art will recognize that DCC is an appropriateactivating agent for coupling of alcohols and carboxylic acids to formesters. One of ordinary skill in the art will recognize that alternateactivating agents are also useful for the coupling of alcohols andcarboxylic acids to form esters. Such alternate activating agentsinclude, but are not limited to, EDC, HBTU, BOP, PyBOP, carbonyldiimidazole, disuccinimidyl carbonate and the like. One of ordinaryskill in the art will further recognize that alternatives to carboxylicacids with activating agents are useful for the formation of esters fromalcohols. Such alternatives include functional reagents that include,and are not limited to, anhydrides, acid chlorides, acyl imidazoles,acyl succinimides and the like. One of ordinary skill in the art willrecognize that alternatives to the benzyl ether protecting group, andassociated reaction conditions for their cleavage, are useful. Variousappropriate alcohol protecting groups are broadly described in “Green'sProtective Groups in Organic Synthesis”. Such benzyl ether alternativesinclude, but are not limited to, trimethylsilyl ethers, tert-butyldimethylsilyl ethers, triisopropylsilyl ethers, tert-butyl diphenylsilylethers, acetates, benzoates, 4-nitrobenzoates, tert-butyl ethers,4-methoxybenzyl ethers and the like.

As illustrated in Scheme 8, a compound of Formula XXII is converted to abenzyl ether giving a compound of Formula XXIII The ketal of a compoundof Formula XXIII is then cleaved giving a compound of Formula X. One ofordinary skill in the art will recognize that alternate reagents andreaction conditions are useful for formation of a benzyl ether. One ofordinary skill in the art will also recognize that alternatives to thebenzyl ether protecting group, and associated reaction conditions fortheir formation, are useful. Various appropriate alcohol protectinggroups are broadly described in “Green's Protective Groups in OrganicSynthesis”. Such benzyl ether alternatives include, but are not limitedto, trimethylsilyl ethers, tert-butyl dimethylsilyl ethers,triisopropylsilyl ethers, tert-butyl diphenylsilyl ethers, acetates,benzoates, 4-nitrobenzoates, tert-butyl ethers, 4-methoxybenzyl ethersand the like. Similarly, one of ordinary skill in the art will recognizethat alternative reaction conditions are useful for the cleavage ofacetals and ketals. Such conditions are generally described in “Green'sProtective Groups in Organic Synthesis”.

As illustrated in Scheme 9, a compound of Formula X is converted to acompound of Formula XXIV. A compound of Formula XXIV is a bis-carbonate,a bis-ester or a bis-carbamate. On hydrogenation, the benzyl ether ofcompound XXIV is cleaved giving a compound of Formula XXV.

One of ordinary skill in the art will recognize that a bis-carbonateversion of a compound of Formula XXIV can be prepared by reacting acompound of Formula X with functional reagents that include, but are notlimited to, chloroformates, pyrocarbonates and the like. One of ordinaryskill in the art will recognize that carbonate formation can include useof bases such as, but not limited to, triethylamine, triisopropylamine,diisopropylethylamine, DBU, N-methylmorpholine, N-methylpyridine,N,N-dimethylpiperazine and the like. One of ordinary skill in the artwill recognize that carbonate formation can include use of acyl transfercatalysts such as, but not limited to, DMAP, pyridine, 2-methylpyridineand the like. One of ordinary skill in the art will recognize thatcarbonate formation can include use of Lewis acid catalysts such as, butnot limited to, zinc chloride, zinc acetate, zinc bromide, aluminumtrichloride, titanium trichloride, titanium isopropoxide, borontrifluoride, tin chloride, alumina, silica gel and the like.

One of ordinary skill in the art will recognize that a bis-acetateversion of a compound of Formula XXIV can be prepared by reacting acompound of Formula X with functional reagents that include, but are notlimited to, anhydrides, acid chlorides, acyl imidazoles, acylsuccinimides and the like. Additionally, one of ordinary skill in theart will recognize that carboxylic acids in the presence of activatingagents will produce similar results. Suitable activating agents include,but are not limited to, DCC, EDC, HBTU, BOP, PyBOP, carbonyldiimidazole, disuccinimidyl carbonate and the like.

One of ordinary skill in the art will recognize that a bis-carbamateversion of a compound of Formula XXIV can be prepared by reacting acompound of Formula X with functional reagents that include, but are notlimited to, isocyanates and the like. One of ordinary skill in the artwill recognize that bases can facilitate carbamate formation. Such basesinclude, but are not limited to, triethylamine, triisopropylamine,diisopropylethylamine, DBU, N-methylmorpholine, N-methylpyridine,N,N-dimethylpiperazine and the like. One of ordinary skill in the artwill recognize that acyl transfer catalysts can facilitate carbamateformation. Such acyl transfer catalysts include, but are not limited to,DMAP, pyridine, 2-methylpyridine and the like. Additionally, one ofordinary skill in the art will recognize that introduction of Lewis acidcatalysts may facilitate carbamate formation. Such Lewis acid catalystsinclude, but are not limited to, zinc chloride, zinc acetate, zincbromide, aluminum trichloride, titanium trichloride, titaniumisopropoxide, boron trifluoride, tin chloride, alumina, silica gel andthe like.

One of ordinary skill in the art will also recognize that alternativesto the benzyl ether protecting group, and associated reaction conditionsfor their cleavage, are useful. Various appropriate alcohol protectinggroups are broadly described in “Green's Protective Groups in OrganicSynthesis”. Such benzyl ether alternatives include, but are not limitedto, trimethylsilyl ethers, tert-butyl dimethylsilyl ethers,triisopropylsilyl ethers, tert-butyl diphenylsilyl ethers, acetates,benzoates, 4-nitrobenzoates, tert-butyl ethers, 4-methoxybenzyl ethersand the like.

As illustrated in Scheme 10, compounds of Formula X are reacted withacetals, ketals, aldehydes or ketones in the presence of an acidcatalyst producing compounds of Formula XXVI. Subsequent cleavage of thebenzyl ether protecting group gives compounds of Formula XV. One ofordinary skill in the art will recognize that for preparation ofcompounds of Formula XXVI alternatives to acetals, ketals, aldehydes orketones will produce similar results. Such alternatives include, but arenot limited to, vinyl ethers and the like. Additionally, one of ordinaryskill in the art will recognize that while p-toluenesulfonic acid is anappropriate acid catalyst for the formation of acetals and ketals,alternative acid catalysts are also useful. Such alternatives top-toluenesulfonic acid include, but are not limited to, PPTS, sulfuricacid, methanesulfonic acid, Amberlyst resin, DOWEX acid resin, silicagel and the like. Furthermore, one of ordinary skill in the art willrecognize that a compound of Formula XXVI can be converted into analternate compound of Formula XXVI on reaction with an alternate acetal,ketal, aldehyde or ketone in the presence of an acid catalyst. One ofordinary skill in the art will recognize that alternatives to the benzylether protecting group, and associated reaction conditions for theircleavage, are useful. Various appropriate alcohol protecting groups arebroadly described in “Green's Protective Groups in Organic Synthesis”.Such benzyl ether alternatives include, but are not limited to,trimethylsilyl ethers, tert-butyl dimethylsilyl ethers,triisopropylsilyl ethers, tert-butyl diphenylsilyl ethers, acetates,benzoates, 4-nitrobenzoates, tert-butyl ethers, 4-methoxybenzyl ethersand the like. One of ordinary skill in the art will recognize that acompound of Formula XV includes a compound of Formula XXII.

As illustrated in Scheme 11, a compound of Formula XXI couples to acompound of Formula XV or a compound of Formula XXV through aphosphodiester linkage. Subsequent salt formation of the phosphodiestergives a compound of Formula XXVII. One of ordinary skill in the art willrecognize that a compound of Formula XXI, a compound of Formula XV and acompound of Formula XXV all contain primary hydroxyl groups. One ofordinary skill in the art will also recognize that formation ofphosphodiesters between two different alcohols is achievable through useof a variety of phosphorus reagents and reaction conditions. Phosphorusreagents useful for the generation of phosphodiesters include, but arenot limited to, POCl3,

and the like. In some instances, the two alcohols are combinedsimultaneously with the phosphorus reagent. In some instances, the twohydroxyl groups are reacted with the phosphorus reagent in sequence. Insome instances, the phosphodiester formation requires additional stepsincluding, but not limited to, oxidation, deprotection or a combinationthereof either executed as single additional steps or as multipleadditional steps. One of ordinary skill in the art will recognize thatbases can facilitate reaction with phosphorus reagents useful forphosphodiester formation. Such bases include, but are not limited to,triethylamine, triisopropylamine, diisopropylethylamine, DBU,N-methylmorpholine, N-methylpyridine, N,N-dimethylpiperazine and thelike. One of ordinary skill in the art will recognize that acyl transfercatalysts can facilitate reaction with phosphorus reagents useful forphosphodiester formation. Such acyl transfer catalysts include, but arenot limited to, DMAP, pyridine, 2-methylpyridine and the like. One ofordinary skill in the art will recognize that useful reagents forphosphodiester salt formation include, but are not limited to, DOWEX Na⁺resin, sodium bicarbonate, sodium carbonate and the like. One ofordinary skill in the art will recognize that compounds of Formula XXVIIinclude compounds 1, 2, 3, 4, 5, 6, 7, 8, 9 and 12.

With reference to Schemes 1-11, one of ordinary skill in the art willrecognize that, collectively, said schemes enable the preparation ofvarious stereoisomers of a compound of Formula 1. Furthermore, one ofordinary skill in the art will recognize that the various forms of thecompounds of this invention include salt forms other than Na. Withreference to different salt forms, compounds of Formula I, wherein R⁴ isas generally defined, can be converted from the OH form or from a givensalt form into an alternate salt form. Reagents useful for such forminterconversions include, but are not limited to, magnesium chloride,calcium chloride and the like. One of ordinary skill in the art willrecognize that, including R⁴ conversion, compounds of Formula XXVIIinclude compounds 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29 and 30.

It is contemplated that any embodiment discussed in this specificationcan be implemented with respect to any method, kit, reagent, orcomposition of the invention, and vice versa. Furthermore, compositionsof the invention can be used to achieve methods of the invention.

EXAMPLES

While certain features of the invention have been illustrated anddescribed herein, many modifications, substitutions, changes, andequivalents will now occur to those of ordinary skill in the art. It is,therefore, to be understood that the appended claims are intended tocover all such modifications and changes as fall within the true spiritof the invention.

In executing the following exemplary synthetic protocols, the followingrelates to particulars relevant to equipment and analytical protocols.HPLC analyses were carried utilizing an)(Bridge C8 column (50×4.6 mm,3.50 with the following method. Solvent A=25% ammonia in water,B=Acetonitrile; Flow Rate: 1 ml/min.

Example 1—Preparation of Sodium (R)-2,3-bis(tetradecanoyloxy)propyl(2,3-diacetoxypropyl) Phosphate (Compound 1)

Acetic anhydride (3.5 ml, 36.3 mmol, 10 equiv) was added to a solutionof DMPG sodium salt (2.5 g, 3.63 mmol) in dry pyridine (50 ml, 20 vol)at room temperature (25° C.) under nitrogen atmosphere. DMAP (88 mg,0.725 mmol, 0.2 equiv) was added to the mixture and heated to 100° C.for 48 h. Upon completion of the reaction (as confirmed by TLC analysis,20% MeOH in DCM, R_(f) ˜0.6, identified by Phosphomolybdic acid stain),the solvent was evaporated, and the crude product was passed throughcolumn chromatography packed with neutral silica gel (230-400 mech).(Note: Silica gel was neutralized by washing with 10% ammonia inmethanol). The product was eluted with dichloromethane containing 10%methanol to afford (R)-2,3-bis(tetradecanoyloxy)propyl(2,3-diacetoxypropyl) phosphate as its ammonium salt. The resultantammonium salt was exchanged to Na salt by passing through a pad ofDowex® 50WX8 Na+ resin in dichloromethane containing 10% methanol. Theproduct fractions were collected and concentrated. The product wasdissolved in a mixture of acetonitrile and water (5 ml:15 ml) andlyophilized to give the sodium salt of(R)-2,3-bis(tetradecanoyloxy)propyl (2,3-diacetoxypropyl) phosphate aslight brown solid. Yield: 1.2 g (44%). ¹H-NMR (400 MHz, DMSO-d₆): δ_(H)4.99-5.05 (m, 2H), 4.20-4.29 (m, 2H), 4.07 (m, 2H), 3.67 (m, 4H), 2.26(t, J=4.49 Hz, 4H), 2.01 (s, 6H), 1.49 (m, 4H), 1.23 (m, 40H), and 0.85(t, J=4.04 Hz, 6H) ppm. ¹³C-NMR (100 MHz, DMSO-d₆): δ_(H) 172.63,172.45, 170.37, 170.08, 71.07, 70.99, 70.89, 63.85, 62.98, 62.81, 33.99,33.83, 31.85, 29.68, 29.62, 29.56, 29.39, 29.35, 29.30, 29.07, 29.00,and 24.94 ppm. LCMS (ELSD): 749.1 (M-23).

Example 2—Preparation of Sodium (R)-2,3-bis (tetradecanoyloxy)propyl((2,2-dimethyl-1,3-dioxolan-4-yl)methyl) Phosphate (Compound 12)

2,2-Dimethoxypropane (7.54 g, 72.5 mmol, 10 equiv) and p-Toluenesulfonicacid (72 mg, 0.378 mmol, 0.052 equiv) was added to a solution of DMPGsodium salt (5 g, 7.25 mmol) in toluene (200 ml, 40 vol). The mixturewas heated to 140° C. for 16 h. The solvent was evaporated and the crudeproduct (5.6 g) was taken for the next step without furtherpurification.

Example 3—Preparation of Sodium (R)-2,3-bis (tetradecanoyloxy)propyl((2-heptadecyl-1,3-dioxolan-4-yl)methyl) Phosphate (Compound 4)

Octadecanaldehyde (4.55 g, 16.97 mmol, 3 equiv) was added to a solutionof crude Compound 12 (4 g, 5.65 mmol) in 1,2-dichloroethane (80 ml, 20vol) at room temperature (25° C.) followed by Amberlyst-15 (800 mg, 20wt %). The mixture was stirred at 80° C. for 48 h. Upon completion ofthe reaction (as confirmed by TLC analysis, 15% MeOH in DCM, R_(f)˜0.4,identified by Phosphomolybdic acid stain), the reaction mixture wasfiltered and washed with aqueous NaHCO₃ solution (1×80 ml). The aqueouslayer was extracted with DCM (3×50 ml) and the combined organic layerswere dried over sodium sulphate. The organic layer was concentrated, andthe crude product was passed through column chromatography packed withneutral silica gel (230-400 mech). (Note: Silica gel was neutralized bywashing with 10% ammonia in methanol). The product was eluted withdichloromethane containing 10-12% methanol to afford (R)-2,3-bis(tetradecanoyloxy)propyl ((2-heptadecyl-1,3-dioxolan-4-yl)methyl)phosphate as its ammonium salt (1.8 g). The (R)-2,3-bis(tetradecanoyloxy)propyl ((2-heptadecyl-1,3-dioxolan-4-yl)methyl)phosphate was further purified by triturating with a mixture of DCM:MeOH(9 ml:90 ml). The resultant solid was filtered and washed with methanol(1×10 ml). The ammonium salt was exchanged to Na salt by passing througha pad of Dowex® 50WX8 Na+ resin using 10% methanol in dichloromethane.The product fractions were collected and concentrated to give the sodium(R)-2,3-bis (tetradecanoyloxy)propyl((2-heptadecyl-1,3-dioxolan-4-yl)methyl) phosphate as off-white solid.Yield: 1.168 g (24.6%, 2 steps). ¹H-NMR (400 MHz, DMSO-d₆): δ_(H) 5.27(m, 1H), 4.97-4.84 (m, 1H), 4.40-4.35 (m, 3H), 4.26-4.12 (m, 2H), 4.07(m, 1H), 4.00-3.96 (m, 1H), 3.87 (m, 1H), 3.68 (m, 1H), 2.31 (t, J=7.40Hz, 4H), 1.61 (m, 6H), 1.26 (m, 70H), and 0.89 (t, J=6.04 Hz, 9H) ppm.¹³C-NMR (100 MHz, CDCl₃): δ_(H) 173.51, 173.40, 105.20, 104.61, 74.47,70.55, 67.11, 66.52, 65.88, 63.94, 62.74, 34.27, 34.15, 34.08, 34.02,31.94, 31.93, 29.83, 29.80, 29.77, 29.75, 29.73, 29.71, 29.68, 29.51,29.46, 29.40, 29.37, 29.30, 29.29, 24.97, 24.88, 24.46, 24.10, 22.69,14.16, and 14.15 ppm.

Example 4—Preparation of Sodium (R)-2,3-bis(tetradecanoyloxy)propyl((2-pentadecyl-1,3-dioxolan-4-yl)methyl) Phosphate (Compound 5)

Hexadecanaldehyde (6.12 g, 25.4 mmol, 3 equiv) was added to a solutionof crude Compound 12 (6 g, 8.42 mmol) in 1,2-dichloroethane (120 ml, 20vol) at room temperature (25° C.). To this was added Amberlyst-15 (1.2g, 20 wt %) and the mixture was stirred at 80° C. for 48 h. Uponcompletion of the reaction (as confirmed by TLC analysis, 15% MeOH inDCM, R_(f)˜0.4, identified by Phosphomolybdic acid stain), the reactionmixture was filtered and washed with aqueous sodium bicarbonate solution(1×100 ml). The aqueous layer was extracted with DCM (3×60 ml) and thecombined organic layer as dried over anhydrous sodium sulphate. Theorganic layer was concentrated, and the crude product was passed througha bed of neutral silica gel (230-400 mech). (Note: Silica gel wasneutralized by washing with 10% ammonia in methanol). The product waseluted with dichloromethane containing 10% methanol to afford(R)-2,3-bis(tetradecanoyloxy)propyl((2-pentadecyl-1,3-dioxolan-4-yl)methyl) phosphate as its ammonium salt.The ammonium salt was exchanged to sodium salt by passing through a padof Dowex® 50WX8 Na+ resin using 10% methanol in dichloromethane. Theproduct fractions were collected and concentrated to give the sodiumsalt of (R)-2,3-bis(tetradecanoyloxy)propyl((2-pentadecyl-1,3-dioxolan-4-yl)methyl) phosphate as off-white solid(1.30 g, 17.3% yield over 2 steps). ¹H-NMR (400 MHz, DMSO-d₆): δ_(H)5.24 (m, 1H), 4.99-4.81 (2 t, J=4.4 Hz, 1H), 4.42 (m, 1H), 4.26-4.17 (m,2H), 4.12-3.65 (m, 6H), 2.34-2.28 (m, 4H), 1.60 (m, 6H), 1.32 (m, 66H),and 0.90 (t, J=7.2 Hz, 9H) ppm. ¹³C-NMR (100 MHz, CDCl₃): δ_(H) 173.59,105.19, 104.63, 74.6, 70.74, 67.22, 66.41, 65.71, 63.58, 62.83, 34.33,34.16, 34.11, 34.05, 31.95, 29.81, 29.79, 29.72, 29.68, 29.51, 29.47,29.41, 29.31, 24.98, 24.90, 24.49, 24.12, 22.70, and 14.09 ppm.

Example 5—Preparation of Sodium (R)-2,3-bis(tetradecanoyloxy)propyl((2-pentyl-1,3-dioxolan-4-yl)methyl) Phosphate (Compound 6)

Hexanal (4.17 ml, 33.94 mmol, 6 equiv) was added to a solution of crudeCompound 12 (4 g, 5.65 mmol) in DCM (80 ml, 20 vol) at room temperature(25° C.). To this was added Amberlyst-15 (800 mg, 20 wt %) and themixture was stirred at room temperature for 16 h. Upon completion of thereaction (as confirmed by TLC analysis, 15% MeOH in DCM, Rf˜0.4,identified by Phosphomolybdic acid stain), the reaction mixture wasfiltered and washed with aqueous sodium bicarbonate solution (80 ml).The aqueous layer was extracted with DCM (3×50 ml) and the combinedorganic layer was dried over anhydrous sodium sulphate. The organiclayer was concentrated under reduced pressure and the crude product waspassed through as plug of neutral silica (230-400 mesh) eluting withdichloromethane containing 10% methanol to afford(R)-2,3-bis(tetradecanoyloxy)propyl ((2-pentyl-1,3-dioxolan-4-yl)methyl)phosphate as its ammonium salt. The resultant ammonium salt wasexchanged to sodium salt by passing through a pad of Dowex® 50WX8 Na+resin using 10% methanol in dichloromethane. The product fractions werecollected and concentrated to give the sodium salt of(R)-2,3-bis(tetradecanoyloxy)propyl ((2-pentyl-1,3-dioxolan-4-yl)methyl)phosphate as light brown sticky solid. Yield: 1.77 g (41.74%). R_(f)=0.4in 10:1.5/DCM:MeOH. ¹H-NMR (400 MHz, DMSO-d₆): δ_(H) 5.08 (m, 1H),4.85-4.77 (m, 1H), 4.28 (m, 1H), 4.09-4.00 (m, 2H), 3.78-3.62 (m, 3H),3.58-3.48 (m, 2H), 2.26 (t, J=5.24 Hz, 4H), 1.50 (m, 6H), 1.27 (m, 47H),and 0.85 (t, J=0.85 Hz, 9H) ppm. ¹³C-NMR (100 MHz, CDCl₃): δ_(H) 173.65,173.57, 105.21, 104.61, 74.64, 74.57, 70.76, 70.69, 67.17, 67.07, 66.36,65.61, 63.54, 62.84, 34.32, 34.11, 34.03, 33.91, 31.95, 31.87, 31.77,29.78, 29.76, 29.71, 29.65, 29.49, 29.45, 29.40, 29.30, and 24.97 ppm.

Example 6—Preparation of Sodium 2,3-bis(butyryloxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl) Phosphate (Compound 7)

Butyric anhydride (8.96 g, 56.61 mmol, 13 equiv) was added to a solutionof DMPG sodium salt (3.0 g, 4.35 mmol) in dry pyridine (60 ml, 20 vol)at room temperature (25° C.) under nitrogen atmosphere. DMAP (1.59 g,13.07 mmol, 3.0 equiv) was added to the mixture in portions and themixture was stirred at room temperature for 20 h. Upon completion of thereaction (as confirmed by TLC and LCMS analysis, 20% MeOH in DCM,R_(f)˜0.6, identified by Phosphomolybdic acid stain), the solvent wasevaporated, and the crude product was passed through a plug of silicagel (230-400 mesh) eluting with dichloromethane containing 10% ofmethanol to afford the product as thick gum. This was diluted with ethylacetate (20 vol) and washed with 1.5N HCl (10 vol) followed by water.The organic layer was then stirred with aqueous NaHCO₃ solution (3 equivin 5 vol of water) at room temperature for 30 min. The organic layer wasseparated, dried over Na₂SO₄ and concentrated under vacuum to get sodium2,3-bis(butyryloxy)propyl ((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate as a thick syrup (1.6 g, 44% yield). ¹H-NMR (400 MHz, CDCl₃):δ_(H) 5.23-5.25 (m, 2H), 4.40-4.43 (m, 2H), 4.18-4.24 (m, 2H), 3.93 (m,4H), 2.28-2.33 (m, 8H), 1.58-1.68 (m, 8H), 1.27-1.33 (m, 40H), and0.95-0.97 (m, 6H) ppm. ¹³C-NMR (100 MHz, CDCl₃): δ_(H) 173.57, 173.45,70.72, 63.51, 62.70, 36.08, 35.91, 34.29, 34.08, 31.94, 29.75, 29.69,29.65, 29.62, 29.45, 29.42, 29.39, 29.26, 29.24, 24.94, 24.87, 22.69,18.31, 18.28, 14.10, 13.62 and 13.57 ppm.

Example 7—Preparation of Sodium 2,3-bis((3-methylbutanoyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl) Phosphate (Compound 8)

Isovaleric anhydride (10.55 g, 56.66 mmol, 13 equiv) was added to asolution of DMPG sodium salt (3.0 g, 4.35 mmol) in dry pyridine (60 ml,20 vol) at room temperature (25° C.) under nitrogen atmosphere. To thiswas added DMAP (1.59 g, 13.07 mmol, 3.0 equiv) in portions and themixture was stirred at room temperature for 20 h. Upon completion of thereaction (as confirmed by TLC and LCMS analysis, 20% MeOH in DCM,R_(f)˜0.6, identified by Phosphomolybdic acid stain), the solvent wasevaporated and the crude product was passed through a plug of silica gel(230-400 mesh) eluting with dichloromethane containing 10% of methanolto afford the product as thick gum. This was diluted with ethyl acetate(20 vol) and washed with 1.5N HCl (10 vol) followed by water. Theorganic layer was then stirred with aqueous NaHCO₃ solution (3 equiv in5 vol of water) at room temperature for 30 min. The organic layer wasseparated, dried over Na₂SO₄ and concentrated under vacuum to get sodium2,3-bis((3-methylbutanoyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl) phosphate as a thick syrup (2.4 g,64% yield). ¹H-NMR (400 MHz, CDCl₃): δ_(H) 5.24-5.29 (m, 2H), 4.40-4.44(m, 2H), 4.18-4.22 (m, 2H), 3.95 (m, 4H), 2.19-2.34 (m, 8H), 2.06-2.12(m, 2H), 1.58-1.61 (m, 4H), 1.27-1.33 (m, 40H), 0.96 (d, J=6.8 Hz, 12H)and 0.90 (t, J=7.2 Hz, 6H) ppm. ¹³C-NMR (100 MHz, CDCl₃): δ_(H) 173.51,173.38, 172.80, 172.71, 70.69, 70.62, 63.59, 62.72, 43.27, 43.07, 34.27,34.07, 31.92, 29.73, 29.67, 29.63, 29.60, 29.44, 29.41, 29.36, 29.25,29.24, 25.50, 24.93, 24.86, 22.67, 22.34, 22.30, and 14.07 ppm. LCMS(ELSD): 833.5 (M-23). Method: Mobile Phase A: 1 ml of 25% ammoniasolution in 1000 ml of MilliQ Water (pH: 9 with Acetic acid). MobilePhase B: acetonitrile. Flow rate: 1.0 ml/min. COLUMN: XBridge C8(50×4.6) mm, 3.5μ. Rt (min): 5.74; Area %-98.84.

Example 8—Preparation of Sodium 2,3-bis(isobutyryloxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl) Phosphate (Compound 9)

Isobutyric anhydride (10.55 g, 56.66 mmol, 13 equiv) was added to asolution of DMPG sodium salt (3.0 g, 4.35 mmol) in dry pyridine (60 ml,20 vol) at room temperature (25° C.) under nitrogen atmosphere. DMAP(1.59 g, 13.07 mmol, 3.0 equiv) was added to this mixture in portions,and the mixture was stirred at room temperature for 20 h. Uponcompletion of the reaction (as confirmed by TLC and LCMS analysis, 20%MeOH in DCM, R_(f)˜0.6, identified by Phosphomolybdic acid stain), thesolvent was evaporated and the crude product was passed through a plugof silica gel (230-400 mesh) eluting with dichloromethane containing 10%of methanol to afford the product as thick gum. This was diluted withethyl acetate (20 vol) and washed with 1.5N HCl (10 vol) followed bywater. The organic layer was then stirred with aqueous NaHCO₃ solution(3 equiv in 5 vol of water) at room temperature for 30 min. The organiclayer was separated, dried over Na₂SO₄ and concentrated under vacuum toget sodium 2,3-bis(isobutyryloxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl) phosphate as a thick syrup (1.6 g,44% yield). ¹H-NMR (400 MHz, CDCl₃): δ_(H) 5.24-5.27 (m, 2H), 4.39-4.44(m, 2H), 4.17-4.23 (m, 2H), 3.94 (m, 4H), 2.52-2.60 (m, 2H), 2.28-2.33(m, 4H), 1.58-1.61 (m, 4H), 1.31-1.33 (m, 40H), 1.32 (t, J=6.8 Hz, 12H)and 0.89 (t, J=7.2 Hz, 6H) ppm. ¹³C-NMR (100 MHz, CDCl₃): δ_(H) 176.74,173.53, 173.41, 70.72, 63.50, 62.73, 34.28, 34.07, 33.93, 33.85, 31.92,29.73, 29.68, 29.62, 29.60, 29.43, 29.39, 29.37, 29.24, 29.22, 24.92,24.86, 22.68, 18.97, and 14.10 ppm.

Example 9—Preparation of Sodium 2,3-bis((ethoxycarbonyl)oxy)propyl((R)-2,3-bis (tetra decanoyloxy)propyl) Phosphate (Compound 2)

To a suspension of DMPG-Na (500.0 g, 0.7258 mol, 1.0 equiv) in toluene(15 vol) was added diethylpyrocarbonate (1176.5 g, 7.258 mol, 10 equiv)followed by anhydrous ZnCl₂ (128.61 g, 0.943 mol, 1.3 equiv) at roomtemperature under nitrogen. The mixture was stirred at 37-40° C. for 30h. After completion of reaction, the reaction mixture was cooled to roomtemperature AND filtered through a thin bed of Celite®. The filtrate wasconcentrated under vacuum maintaining the bath temperature below 40° C.The sticky residue was dissolved in EtOAc (30 vol) and washed with water(5 vol×2). The organic layer was dried over Na₂SO₄ and concentratedunder vacuum maintaining the bath temperature below 45° C. to get asticky residue. The crude product (680 g) was purified by silica gelcolumn chromatography (230-400 mesh) using 5-20% of MeOH indichloromethane as gradient. The product fractions were concentrated toget 385 g of pure product. This was dissolved in a mixture of EtOAc andwater (15:3 vol)) and cooled to ˜5° C. To this was added HCl solution(0.5N, 2 equiv) and the mixture was stirred for 15-20 minutes at ˜5° C.The organic layer was separated and washed with 0.5N HCl (3 vol×1) andwater (5 vol×1). The organic layer was slowly basified with NaHCO₃solution (4 equiv in 5 vol of water) at room temperature. The mixturewas stirred for 2 h and the organic layer was separated, dried overNa₂SO₄ and concentrated to get sodium 2,3-bis((ethoxycarbonyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl) phosphate as a thick syrup (300.0g, 49% yield). ¹H-NMR (400 MHz, CDCl₃): δ_(H) 5.23-5.25 (m, 1H),5.10-5.11 (m, 1H), 4.49-4.36 (m, 2H), 4.35-4.16 (m, 6H), 4.03-3.91 (m,4H), 2.34-2.28 (m, 4H), 1.61-1.57 (m, 4H), 1.35-1.27 (m, 46H), and 0.89(t, J=68 Hz, 6H) ppm. ¹³C-NMR (100 MHz, CDCl₃): δ_(H) 173.56, 173.50154.97, 154.77, 154.73, 74.51, 74.44, 70.71, 70.64, 65.88, 64.48, 64.41,64.23, 63.55, 63.20, 62.74, 34.25, 34.04, 31.93, 29.76, 29.74, 29.70,29.66, 29.62, 29.46, 29.42, 29.39, 29.26, 29.23, 24.93, 24.86, 22.69,and 14.10 ppm.

Example 10—Preparation ofMagnesium-2,3-bis((ethoxycarbonyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)Phosphate (Compound 10)

A solution of magnesium chloride (0.571 g, 6.00 mmol, 0.5 equiv) inwater (10 vol) was added to sodium 2,3-bis((ethoxycarbonyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl) phosphate (10 g, 12.00 mmol, 1.0equiv) in ethanol (100 ml), and the mixture was stirred at roomtemperature for 14 h. The mixture was diluted with water (200 ml) andthe precipitate was filtered, washed with water (100 ml) and dried undervacuum to affordmagnesium-2,3-bis((ethoxycarbonyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate as an off-white solid (8.0 g, 79% yield). ¹H-NMR (400 MHz,CDCl₃): δ_(H) 5.27 (m, 1H), 5.13 (m, 1H), 4.50-4.00 (m, 14H), 2.34-2.28(m, 4H), 1.60-1.59 (m, 4H), 1.35 (m, 46H), and 0.89 (t, J=6.4 Hz, 6H)ppm. ¹³C-NMR (100 MHz, CDCl₃): δ_(H) 173.50, 173.31, 154.91, 154.60,74.21, 70.31, 65.84, 64.35, 64.19, 63.96, 63.60, 62.70, 34.15, 34.00,31.92, 29.75, 29.68, 29.66, 29.62, 29.48, 29.43, 29.37, 29.26, 29.22,24.91, 22.67, 14.13 and 14.07 ppm.

Example 11—Preparation of Calcium-2,3-bis((ethoxycarbonyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl) Phosphate (Compound 11)

A solution of calcium chloride (0.666 g, 6.00 mmol, 0.5 equiv) in water(10 vol) was added to a solution of sodium2,3-bis((ethoxycarbonyl)oxy)propyl ((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate (10 g, 12.00 mmol, 1.0 equiv) in ethanol (100 ml) at roomtemperature and the mixture was stirred at room temperature for 14 h.The mixture was diluted with water (200 ml) and the precipitate wasfiltered, washed with water (100 ml) and dried under vacuum to affordcalcium-2,3-bis((ethoxycarbonyl)oxy)propyl((R)-2,3-bis(tetradecanoyloxy)propyl)phosphate as an off white solid (8.2 g, 83% yield). ¹H-NMR (400 MHz,CDCl₃): δ_(H) 5.28 (m, 1H), 5.19 (m, 1H), 4.51-4.40 (m, 2H), 4.36-4.14(m, 6H), 3.90-4.10 (m, 4H), 2.34-2.28 (m, 4H), 1.59 (m, 4H), 1.33-1.27(m, 46H), and 0.89 (t, J=6.8 Hz, 6H) ppm. ¹³C-NMR: (100 MHz, CDCl₃):δ_(H) 173.54, 154.99, 74.44, 70.59, 68.70, 65.95, 64.49, 64.26, 63.92,62.71, 34.17, 34.00, 31.91, 29.74, 29.72, 29.67, 29.61, 29.46, 29.42,29.37, 29.25, 29.20, 24.88, 24.80, 22.66, 14.11 and 14.05 ppm.

Example 12—Cardiac Response Testing

Efficacy evaluation of the compounds of the present invention involvedECG measurements of adult male Hartley guinea pigs wherein PR, QRS, QT,QTc, JT, RR were recorded. In typical experiments, subcutaneous KahaTR50B bio potential telemeters were surgically implanted in adult maleHartley guinea pigs weighing 300 to 350 g at enrollment. One lead wassutured to the apex of the heart, while another was sutured to the sideof the aorta. The animals were allowed to recover from surgery for 5days prior to being returned to the testing colony. Following recovery,animals were subjected to two rounds of evaluation as follows:

In Round 1 of the testing, baseline ECG records were obtained for 5minutes prior to exposing the animals to single oral doses ofmoxifloxacin (20 mg/kg), administered orally to 8 guinea pigs. ECGsignals were acquired continuously for 6 hours post administration ofmoxifloxacin. The animals were then returned to their housing to washoutthe drug over 5 to 7 days.

In Round 2 of the testing of the 8 guinea pigs, baseline ECGs wereobtained for 5 minutes to compare these baseline intervals with theintervals measured prior to the 1st exposure to moxifloxacin (above).The animals were administered a single oral dose of 2 mg/kg of testcompound (selected from Compounds 1-12). Concomitantly, 6 animals weregavaged with the same batch of moxifloxacin (20 mg/kg). Another 2animals were given moxifloxacin (20 mg/kg) only. The purpose of dosingthese animals with moxifloxacin only was to verify whether a 2ndexposure to moxifloxacin would result in enhanced QT prolongation. ECGswere acquired continuously for 6 hours. The animals were then returnedto their housing to washout the drug over 5 to 7 days.

ECG analysis over 5 minutes pre-dose and 6 hours post dose consisted inwas automated based on pattern recognition algorithms. The analyzed datawere binned into 5-minute segments. Intervals such as PR, QRS, QT, QTc,JT and RR were analyzed automatically using AD Instruments LabChart Prov8. The accuracy of the measurements was verified manually using digitalcursors by randomly selecting 3 to 5 segments at any given timepostdose. There were no noted discrepancies between automated and manualintervals outside of arrhythmic episodes. The frequency of arrhythmiawas quantified and expressed as “% of ECG time spent in abnormal sinusrhythm over entire duration of the recording”.

The table below list the protection observed by test compounds againstMoxifloxacin-induced QTc prolongation.

Moxifloxacin Test Compound 40 mg/kg 6 4 2 1 5 11* 10* 7* 8* 9*Protection indicated as percent (%) of Moxifloxacin effect Protection atn/a 74 95 95 118 35 83 83 83 74 91 1 h post dose Protection at n/a 11088 88 122 113 94 88 100 97 94 2 h post dose Protection at n/a 115 22 22100 126 91 72 119 100 100 4 h post dose Protection at n/a 138 90 90 116176 116 116 147 132 116 6 h post dose Time of n/a 2 h 2 h 2 h 2 h 2 h 2h 2 h 2 h 2 h 2 h maximal protection Duration of n/a 6 h 4 h 4 h 6 h 6 h6 h 6 h 6 h 6 h 6 h complete protection Onset of n/a 1 h 1 h 1 h 1 h 2 h1 h 1 h 1 h 1 h 1 h protection Maximal 29 ms 3 ms 8 ms 4 ms 0 ms 0 ms 8ms 2 ms 4 ms 2 ms 3 ms prolongation *Data for these compounds arepreliminary

It will be understood that particular embodiments described herein areshown by way of illustration and not as limitations of the invention.The principal features of this invention can be employed in variousembodiments without departing from the scope of the invention. Thoseskilled in the art will recognize or be able to ascertain using no morethan routine experimentation, numerous equivalents to the specificprocedures described herein. Such equivalents are considered to bewithin the scope of this invention and are covered by the claims.

All publications and patent applications mentioned in the specificationare indicative of the level of skill of those skilled in the art towhich this invention pertains. All publications and patent applicationsare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

All of the compositions and/or methods disclosed and claimed herein canbe made and executed without undue experimentation in light of thepresent disclosure. While the compositions and methods of this inventionhave been described in terms of preferred embodiments, it will beapparent to those of skill in the art that variations may be applied tothe compositions and/or methods and in the steps or in the sequence ofsteps of the method described herein without departing from the concept,spirit and scope of the invention. All such similar substitutes andmodifications apparent to those skilled in the art are deemed to bewithin the spirit, scope and concept of the invention as defined by theappended claims.

To aid the Patent Office, and any readers of any patent issued on thisapplication in interpreting the claims appended hereto, applicants wishto note that they do not intend any of the appended claims to invokeparagraph 6 of 35 U.S.C. § 112, U.S.C. § 112 paragraph (f), orequivalent, as it exists on the date of filing hereof unless the words“means for” or “step for” are explicitly used in the particular claim.

For each of the claims, each dependent claim can depend both from theindependent claim and from each of the prior dependent claims for eachand every claim so long as the prior claim provides a proper antecedentbasis for a claim term or element.

What is claimed is:
 1. A compound of Formula:


2. The compound of claim 1, wherein the compound is a single entity, asolvate, a hydrate, a crystal, an amorphous solid, a liquid or an oil.3. The compound of claim 1, wherein the compound is formulated with oneor more agents that induce a cardiopathy as a side effect.
 4. Thecompound of claim 1, wherein the compound is formulated into apharmaceutical composition.
 5. The compound of claim 4, wherein one ormore agents that induces a cardiopathy as a side effect is selected fromat least one of: Albuterol, Alfuzosin, Amantadine, Amiodarone,Amisulpride, Amitriptyline, Amoxapine, Amphetamine, Anagrelide,Apomorphine, Arformoterol, Aripiprazole, Arsenic trioxide, Astemizole,Atazanavir, Atomoxetine, Azithromycin, Bedaquiline, Bepridil,Bortezomib, Bosutinib, Chloral hydrate, Chloroquine, Chlorpromazine,Ciprofloxacin, Cisapride, Citalopram, Clarithromycin, Clomipramine,Clozapine, Cocaine, Curcumin, Crizotinib, Dabrafenib, Dasatinib,Desipramine, Dexmedetomidine, Dexmethylphenidate, Dextroamphetamine,Amphetamine, Dihydroartemisinin and Piperaquine, Diphenhydramine,Diisopyramide, Dobutamine, Dofetilide, Dolasetron, Domperidone,Dopamine, Doxepin, Dronedarone, Droperidol, Ephedrine, Epinephrine,Adrenaline, Eribulin, Erythromycin, Escitalopram, Famotidine, Felbamate,Fenfluramine, Fingolimod, Flecainide, Fluconazole, Fluoxetine,Formoterol, Foscarnet, Fosphenytoin, Furosemide, Frusemide, Galantamine,Gatifloxacin, Gemifloxacin, Granisetron, Halofantrine, Haloperidol,Hydrochlorothiazide, Ibutilide, Iloperidone, Imipramine, Melipramine,Indapamide, Isoproterenol, Isradipine, Itraconazole, Ivabradine,Ketoconazole, Lapatinib, Levalbuterol, Levofloxacin, Levomethadyl,Lisdexamfetamine, Lithium, Mesoridazine, Metaproterenol, Methadone,Methamphetamine, Methylphenidate, Midodrine, Mifepristone, Mirabegron,Mirtazapine, Moexipril/HCTZ, Moxifloxacin, Nelfinavir, Nicardipine,Nilotinib, Norepinephrine, Norfloxacin, Nortriptyline, Ofloxacin,Olanzapine, Ondansetron, Oxytocin, Paliperidone, Paroxetine,Pasireotide, Pazopanib, Pentamidine, Perflutren lipid microspheres,Phentermine, Phenylephrine, Phenylpropanolamine, Pimozide, Posaconazole,Probucol, Procainamide, Promethazine, Protriptyline, Pseudoephedrine,Quetiapine, Quinidine, Quinine sulfate, Ranolazine, Rilpivirine,Risperidone, Ritodrine, Ritonavir, Roxithromycin, Salbutamol,Salmeterol, Saquinavir, Sertindole, Sertraline, Sevoflurane,Sibutramine, Solifenacin, Sorafenib, Sotalol, Sparfloxacin, Sulpiride,Sunitinib, Tacrolimus, Tamoxifen, Telaprevir, Telavancin, Telithromycin,Terbutaline, Terfenadine, Tetrabenazine, Thioridazine, Tizanidine,Tolterodine, Toremifene, Trazodone, Trimethoprim-Sulfa, Trimipramine,Vandetanib, Vardenafil, Vemurafenib, Venlafaxine, Voriconazole,Vorinostat, or Ziprasidone.
 6. The compound of claim 1, wherein thepharmaceutical composition further comprises one or more excipients,binders, anti-adherents, coatings, disintegrants, fillers, flavors,dyes, colors, glidants, lubricants, preservatives, sorbents, sweeteners,derivatives thereof, or combinations thereof.
 7. The compound of claim6, wherein the binder is selected from the group consisting ofhydroxypropylmethylcellulose, ethyl cellulose, povidone, acrylic andmethacrylic acid co-polymers, pharmaceutical glaze, gums, and milkderivatives.
 8. The compound of claim 4, wherein the pharmaceuticalcomposition comprises a compound of Formula I in an amount per unit doseof between about 1 mg and about 1 gram per unit dose.
 9. The compound ofclaim 4, wherein the pharmaceutical composition is a formulation fororal, sublingual, transdermal, suppository, intrathecal, enteral,parenteral, intravenous, intraperitoneal, cutaneous, subcutaneous,topical, pulmonary, rectal, vaginal, or intramuscular administration.10. The compound of claim 1, wherein the compound is formulated for oraladministration is a tablet, capsule, caplet, pill, powder, troche,lozenge, slurry, liquid solution, suspension, emulsion, elixir or oralthin film (OTF).
 11. The compound of claim 1, wherein the formulation isa solid form, a solution, a suspension, or a soft gel form.
 12. A methodof preparing a compound of Formula I

comprising the steps of: converting the hydroxyl groups of a compound ofFormula II to butyrate esters

wherein, R1 is H, Li, Na or K; and converting a phosphorus-bound OH orONa group to R2, wherein R2 is Mg2+ and wherein said Mg2+ forms an ionicbridge between 2 phosphate units; or comprising the steps of: linking acompound of Formula III with a compound of Formula IV or with a compoundof Formula V through creation of a phosphate diester bridge

and converting a phosphorus-bound OH or ONa group to OR2, wherein R4 isMg2+ and wherein said Mg2+ forms an ionic bridge between two phosphateunits.
 13. The method of claim 12, wherein the method produces compoundsthat individually exist as a single entity, a solvate, a hydrate, acrystal, an amorphous solid, a liquid, or an oil.
 14. A pharmaceuticalcomposition comprising: a compound of Formula I:

and a pharmaceutically acceptable diluent or carrier.
 15. Thepharmaceutical composition of claim 14, wherein the compound of FormulaI exists as a single entity, a solvate, a hydrate, a crystal, anamorphous solid, a liquid or an oil.
 16. The pharmaceutical compositionof claim 14, wherein the pharmaceutical composition further comprisesone or more agents that induce a cardiopathy as a side effect.
 17. Thepharmaceutical composition of claim 16, wherein one or more agents thatinduces a cardiopathy as a side effect is selected from at least one of:Albuterol, Alfuzosin, Amantadine, Amiodarone, Amisulpride,Amitriptyline, Amoxapine, Amphetamine, Anagrelide, Apomorphine,Arformoterol, Aripiprazole, Arsenic trioxide, Astemizole, Atazanavir,Atomoxetine, Azithromycin, Bedaquiline, Bepridil, Bortezomib, Bosutinib,Chloral hydrate, Chloroquine, Chlorpromazine, Ciprofloxacin, Cisapride,Citalopram, Clarithromycin, Clomipramine, Clozapine, Cocaine, Curcumin,Crizotinib, Dabrafenib, Dasatinib, Desipramine, Dexmedetomidine,Dexmethylphenidate, Dextroamphetamine, Amphetamine, Dihydroartemisininand Piperaquine, Diphenhydramine, Diisopyramide, Dobutamine, Dofetilide,Dolasetron, Domperidone, Dopamine, Doxepin, Dronedarone, Droperidol,Ephedrine, Epinephrine, Adrenaline, Eribulin, Erythromycin,Escitalopram, Famotidine, Felbamate, Fenfluramine, Fingolimod,Flecainide, Fluconazole, Fluoxetine, Formoterol, Foscarnet,Fosphenytoin, Furosemide, Frusemide, Galantamine, Gatifloxacin,Gemifloxacin, Granisetron, Halofantrine, Haloperidol,Hydrochlorothiazide, Ibutilide, Iloperidone, Imipramine, Melipramine,Indapamide, Isoproterenol, Isradipine, Itraconazole, Ivabradine,Ketoconazole, Lapatinib, Levalbuterol, Levofloxacin, Levomethadyl,Lisdexamfetamine, Lithium, Mesoridazine, Metaproterenol, Methadone,Methamphetamine, Methylphenidate, Midodrine, Mifepristone, Mirabegron,Mirtazapine, Moexipril/HCTZ, Moxifloxacin, Nelfinavir, Nicardipine,Nilotinib, Norepinephrine, Norfloxacin, Nortriptyline, Ofloxacin,Olanzapine, Ondansetron, Oxytocin, Paliperidone, Paroxetine,Pasireotide, Pazopanib, Pentamidine, Perflutren lipid microspheres,Phentermine, Phenylephrine, Phenylpropanolamine, Pimozide, Posaconazole,Probucol, Procainamide, Promethazine, Protriptyline, Pseudoephedrine,Quetiapine, Quinidine, Quinine sulfate, Ranolazine, Rilpivirine,Risperidone, Ritodrine, Ritonavir, Roxithromycin, Salbutamol,Salmeterol, Saquinavir, Sertindole, Sertraline, Sevoflurane,Sibutramine, Solifenacin, Sorafenib, Sotalol, Sparfloxacin, Sulpiride,Sunitinib, Tacrolimus, Tamoxifen, Telaprevir, Telavancin, Telithromycin,Terbutaline, Terfenadine, Tetrabenazine, Thioridazine, Tizanidine,Tolterodine, Toremifene, Trazodone, Trimethoprim-Sulfa, Trimipramine,Vandetanib, Vardenafil, Vemurafenib, Venlafaxine, Voriconazole,Vorinostat, or Ziprasidone.
 18. The pharmaceutical composition of claim14, wherein the pharmaceutical composition further comprises one or moreexcipients, binders, anti-adherents, coatings, disintegrants, fillers,flavors, dyes, colors, glidants, lubricants, preservatives, sorbents,sweeteners, derivatives thereof, or combinations thereof.
 19. Thepharmaceutical composition of claim 18, wherein the binder is selectedfrom the group consisting of hydroxypropylmethylcellulose, ethylcellulose, povidone, acrylic and methacrylic acid co-polymers,pharmaceutical glaze, gums, and milk derivatives.
 20. The pharmaceuticalcomposition of claim 14, wherein the pharmaceutical compositioncomprises a compound of Formula I in an amount per unit dose of betweenabout 1 mg and about 1 gram per unit dose.
 21. The pharmaceuticalcomposition of claim 14, wherein the pharmaceutical composition is aformulation for oral, sublingual, transdermal, suppository, intrathecal,enteral, parenteral, intravenous, intraperitoneal, cutaneous,subcutaneous, topical, pulmonary, rectal, vaginal, or intramuscularadministration.
 22. The pharmaceutical composition of claim 21, whereinthe formulation for oral administration is a tablet, capsule, caplet,pill, powder, troche, lozenge, slurry, liquid solution, suspension,emulsion, elixir or oral thin film (OTF).
 23. The pharmaceuticalcomposition of claim 14, wherein the formulation is a solid form, asolution, a suspension, or a soft gel form.
 24. A method of reducing oreliminating one or more of a cardiac channelopathy, cardiac muscledamage, or a condition resulting from the irregularity or alteration inthe cardiac pattern, in a human or animal subject, comprising the stepof administering to the human or animal subject one or more of acompound of Formula I


25. The method of claim 24, wherein the compound of Formula I exists asa single entity, a solvate, a hydrate, a crystal, an amorphous solid, aliquid or an oil.
 26. The method of claim 24, wherein the compound ofFormula I reduces or eliminates one or more of a cardiac channelopathyor a condition resulting from the irregularity or alteration in thecardiac pattern caused by the active agent used to treat a disease. 27.The method of claim 24, wherein the compound of Formula I isadministered in an amount per unit dose of between about 1 mg and about1 gram.
 28. The method of claim 24, wherein the compound of Formula I isformulated for oral, sublingual, transdermal, suppository, intrathecal,enteral, parenteral, intravenous, intraperitoneal, cutaneous,subcutaneous, topical, pulmonary, rectal, vaginal, or intramuscularadministration.
 29. The method of claim 24, wherein the compound ofFormula I is formulated for oral administration as a tablet, capsule,caplet, pill, powder, troche, lozenge, slurry, liquid solution,suspension, emulsion, elixir or oral thin film (OTF).
 30. The method ofclaim 24, wherein the compound of Formula I is formulated as a solidform, a solution, a suspension, or a soft gel form.
 31. The method ofclaim 30, wherein the solid form further comprises one or moreexcipients, binders, anti-adherents, coatings, disintegrants, fillers,flavors, dyes, colors, glidants, lubricants, preservatives, sorbents,sweeteners, derivatives thereof, or combinations thereof.
 32. The methodof claim 24, wherein the compound of Formula I is co-administered withone or more agents that induce a cardiopathy as a side effect.
 33. Themethod of claim 32, wherein the one or more active agent that induce acardiopathy as a side effect are selected from at least one of:Albuterol, Alfuzosin, Amantadine, Amiodarone, Amisulpride,Amitriptyline, Amoxapine, Amphetamine, Anagrelide, Apomorphine,Arformoterol, Aripiprazole, Arsenic trioxide, Astemizole, Atazanavir,Atomoxetine, Azithromycin, Bedaquiline, Bepridil, Bortezomib, Bosutinib,Chloral hydrate, Chloroquine, Chlorpromazine, Ciprofloxacin, Cisapride,Citalopram, Clarithromycin, Clomipramine, Clozapine, Cocaine, Curcumin,Crizotinib, Dabrafenib, Dasatinib, Desipramine, Dexmedetomidine,Dexmethylphenidate, Dextroamphetamine, Amphetamine, Dihydroartemisininand Piperaquine, Diphenhydramine, Diisopyramide, Dobutamine, Dofetilide,Dolasetron, Domperidone, Dopamine, Doxepin, Dronedarone, Droperidol,Ephedrine, Epinephrine, Adrenaline, Eribulin, Erythromycin,Escitalopram, Famotidine, Felbamate, Fenfluramine, Fingolimod,Flecainide, Fluconazole, Fluoxetine, Formoterol, Foscarnet,Fosphenytoin, Furosemide, Frusemide, Galantamine, Gatifloxacin,Gemifloxacin, Granisetron, Halofantrine, Haloperidol,Hydrochlorothiazide, Ibutilide, Iloperidone, Imipramine, Melipramine,Indapamide, Isoproterenol, Isradipine, Itraconazole, Ivabradine,Ketoconazole, Lapatinib, Levalbuterol, Levofloxacin, Levomethadyl,Lisdexamfetamine, Lithium, Mesoridazine, Metaproterenol, Methadone,Methamphetamine, Methylphenidate, Midodrine, Mifepristone, Mirabegron,Mirtazapine, Moexipril/HCTZ, Moxifloxacin, Nelfinavir, Nicardipine,Nilotinib, Norepinephrine, Norfloxacin, Nortriptyline, Ofloxacin,Olanzapine, Ondansetron, Oxytocin, Paliperidone, Paroxetine,Pasireotide, Pazopanib, Pentamidine, Perflutren, Phentermine,Phenylephrine, Phenylpropanolamine, Pimozide, Posaconazole, Probucol,Procainamide, Promethazine, Protriptyline, Pseudoephedrine, Quetiapine,Quinidine, Quinine sulfate, Ranolazine, Rilpivirine, Risperidone,Ritodrine, Ritonavir, Roxithromycin, Salbutamol, Salmeterol, Saquinavir,Sertindole, Sertraline, Sevoflurane, Sibutramine, Solifenacin,Sorafenib, Sotalol, Sparfloxacin, Sulpiride, Sunitinib, Tacrolimus,Tamoxifen, Telaprevir, Telavancin, Telithromycin, Terbutaline,Terfenadine, Tetrabenazine, Thioridazine, Tizanidine, Tolterodine,Toremifene, Trazodone, Trimethoprim-Sulfa, Trimipramine, Vandetanib,Vardenafil, Vemurafenib, Venlafaxine, Voriconazole, Vorinostat, orZiprasidone.
 34. The method of claim 24, wherein the compound of FormulaI reduces or eliminates cardiopathies, such as QT prolongation, cardiacmuscle damage, or AV block, that are drug-induced or caused by a diseaseor condition.